Harnessing platinum(IV) prodrugs as versatile photoinitiators and photocrosslinkers for multifunctional hydrogels and protein labeling

Xu, Jiaqian; Zhou, Qiyuan; Sun, Guohan; Liu, Gongyuan; Chen, Shu; Yue, Zhao; Ng, Ka-Yan; Yao, Houzong; Li, Fu Shing; Peng, Yung-Kang; Zhu, Guangyu

doi:10.1038/s41467-025-63958-2

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Published: 06 October 2025

Harnessing platinum(IV) prodrugs as versatile photoinitiators and photocrosslinkers for multifunctional hydrogels and protein labeling

Jiaqian Xu^1,2,
Qiyuan Zhou^1,2,
Guohan Sun¹,
Gongyuan Liu^1,2,
Shu Chen^1,2,
Zhao Yue^1,2,
Ka-Yan Ng^1,2,
Houzong Yao^1,2,
Fu Shing Li¹,
Yung-Kang Peng ORCID: orcid.org/0000-0001-9590-6902¹ &
…
Guangyu Zhu ORCID: orcid.org/0000-0002-4710-7070^1,2

Nature Communications volume 16, Article number: 8879 (2025) Cite this article

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Abstract

Photoresponsive molecules have revolutionized the fields of chemistry, biology, and medicine by enabling precise spatiotemporal control through external light stimuli. While extensive efforts have been employed to investigate the photochemical properties of Pt(IV) coordination complexes, their biomedical applications are still limited to chemotherapeutic functions. Herein, the photochemistry of clinical drug-based Pt(IV) prodrugs is investigated. Surprisingly, Pt(IV) complexes, rather than their Pt(II) counterparts, exhibit rapid photolysis upon irradiation at 365 nm, generating various reactive species including ROS and platinum radicals. Exploiting these unique photolysis products, we demonstrate alternative uses of Pt(IV) prodrugs as photoinitiators, enabling facile fabrication of multifunctional macromolecular materials such as antibacterial and conductive hydrogels for motion sensing. Efficient protein crosslinking further suggests that Pt(IV) coordination complexes can be employed as photocrosslinkers for gelatin hydrogelation and as reagents for protein photoreactive labeling. This comprehensive investigation significantly broadens the biomedical applications of Pt(IV) complexes beyond anticancer prodrugs, expanding the current repertoire of phototriggered biomedical applications using metal complexes. Our findings offer an avenue to harness the untapped potential of Pt(IV) prodrugs, paving the way for the development of advanced photoresponsive systems with diverse biomedical and material applications.

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Introduction

Significant advancements in light-related techniques have been achieved in recent years. The use of external light offers precise control over where and when a process is initiated^1,2. Modern technological advancements in lasers and fiber optics facilitate these techniques towards practical biomedical applications from precision tools in chemical biology, such as bioimaging reagents and protein photocrosslinkers, to therapeutic modalities, including photodynamic and photothermal therapies^3,4,5. As a result, there have been widespread efforts to develop photoresponsive molecules that can efficiently convert light into chemical energy⁶. Among them, transition-metal complexes attract increasing attention owing to their distinctive and fine-tunable ground and excited states resulting from the nature of the central metal, the ligands, and their specific interactions^7,8,9. Metals at different oxidation states exhibit variant chemical or even biological properties¹⁰; however, the photochemical properties of metals at different oxidation states have been scarcely studied.

Despite the great success of Pt(II)-based chemotherapeutics, including cisplatin, carboplatin, and oxaliplatin, that are used in clinics for cancer treatments^11,12, concerns about their severe side effects caused by nonspecific binding as well as acquired resistance limit their clinical applications¹³. In an effort to address these issues, Pt(IV) complexes as prodrugs have been extensively explored. Upon two-electron oxidation, square-planar Pt(II) species are oxidized to octahedral Pt(IV) complexes¹⁴. With the low-spin d⁶ electron configuration, Pt(IV) complexes are more kinetically inert toward ligand substitution, which significantly minimizes the undesirable side reactions with biomolecules prior to DNA binding¹⁰. Reduction to active Pt(II) species inside cancer cells is required for Pt(IV) prodrugs to exert their bioactivities¹⁵.

The photoreactivity of Pt(IV) complexes has been known for decades. Widespread efforts have been devoted to the investigation of photochemical properties of Pt(IV) complexes in diverse applications, such as synthesis¹⁶, solar energy conversion¹⁷, and most notably, chemotherapy^18,19. For example, photosensitive ligands, including iodo and azido groups^20,21, and more recently, photoabsorbers^22,23,24,25, have been exploited to construct small-molecule photoactivatable Pt(IV) prodrugs. Such prodrugs would allow precise control of the Pt(IV) reduction in a spatiotemporal manner to minimize undesirable damage to normal tissue²⁶. Despite these achievements, current research primarily focuses on the release of cytotoxic Pt(II) species for therapeutic purposes within the biomedical sector. The broader applications of photochemical behaviors of Pt(IV) complexes, particularly their untapped potential in other biomedical applications, remain underexplored.

Herein, the photochemical properties of clinical drug-based Pt(IV) complexes containing innocent axial ligands were investigated. In contrast to their kinetic inertness in the dark, Pt(IV) complexes, rather than their Pt(II) counterparts, photolyzed rapidly by UV light, yielding various reactive radical species. Alternative applications of Pt(IV) prodrugs as photoinitiators and photocrosslinkers to fabricate macromolecular scaffolds, such as multipurpose hydrogels, and as protein photolabeling reagents, were subsequently explored. Our findings may not only provide a broader insight into the photochemistry of Pt(IV) prodrugs but also expand the current toolbox of photo-triggered biomedical applications using metal complexes.

Results

Design and synthesis of Pt(IV) prodrugs

We began our study with the chemical design and synthesis of Pt(IV) prodrugs. The three most representative Pt(II) anticancer drugs, including cisplatin, carboplatin, and oxaliplatin, that are used in clinics worldwide, as well as transplatin, were selected as the basic equatorial cores of the Pt(IV) structures²⁷. Simple molecular scaffolds lacking strong absorbance at 365 nm, such as acetic acid, succinic acid, and succinic ester, were selected as innocent axial ligands. Subsequently, six Pt(IV) complexes were readily obtained by functionalizing the hydroxyl group of dihydroxido Pt(IV) species with anhydrides or NHS esters via the most common carboxylate linkage (Fig. 1a and Supplementary Fig. 1)²⁸. The synthesized complexes were fully characterized by electrospray ionization high-resolution mass spectrometry (ESI-HRMS) and multinuclear NMR spectroscopy (¹H, ¹³C, and ¹⁹⁵Pt); their purities were determined by analytical reversed-phase HPLC (RP-HPLC, 254 nm; > 95%) prior to their use in the subsequent experiments (Supplementary Figs. 2–25).

**Fig. 1: Pt(IV) prodrugs photolyzed rapidly upon UV irradiation.**

Photolysis of platinum complexes

With these platinum complexes in hand, we first examined their photolysis properties in water using HPLC. Upon irradiation by 365 nm UV light (Supplementary Fig. 26) at a power density of 9.8 mW/cm² for 10 min, the peak height of all Pt(IV) complexes in the HPLC chromatogram decreased significantly (Fig. 1b, c and Supplementary Fig. 27), and various new species emerged, indicating the rapid photolysis of the Pt(IV) complexes. For example, only 1.2%, 0.6%, and 1.9% of cisPt(IV)−1, cisPt(IV)−2, and cisPt(IV)−3 remained, respectively. In contrast, the corresponding Pt(II) drugs were relatively resistant to photolysis; for instance, 75% of cisplatin and 99% of oxaliplatin remained stable under this condition (Fig. 1b, c and Supplementary Fig. 28). A similar effect was also observed for transplatin and transPt(IV) (Fig. 1c and Supplementary Figs. 27 and 28), aligning with their higher absorbance in the UVA region exhibited by Pt(IV) complexes (Supplementary Fig. 29). The complexity of the photolysis products could be attributed to the continuous exposure to light during the analysis, resulting in successive photolysis of the initial photoproducts. The formation of Pt(II) counterparts and their hydrolyzed products from the Pt(IV) complexes with a cis geometry was confirmed using LC-HRMS (Fig. 1d and Supplementary Fig. 30).

Mechanistic studies on photolysis process

Previous studies have indicated that a radical-forming mechanism is involved in the photolysis of hexahalide- and azido-Pt(IV) complexes^29,30,31. As a proof of concept, the generation of radicals following photolysis of our Pt(IV) complexes based on clinically used Pt(II) drugs was first determined using methylene blue (MB) degradation experiments, a commonly used method to probe oxidative reactive radical species³². In contrast to the relative kinetic inertness of Pt(IV) complexes themselves in the dark, MB was readily degraded upon irradiation in the Pt(IV) complex-treated groups, while it remained intact in Pt(II) complex-treated samples, indicating the production of reactive radical species following the photolysis of Pt(IV) complexes but not the Pt(II) counterparts (Fig. 2a and Supplementary Fig. 31). A similar effect was also observed for transplatin and transPt(IV), where the degradation of MB was significant in the transPt(IV) group (Supplementary Fig. 31d, h), implying that the oxidation state rather than the coordination geometry of the metal determines the ability to generate reactive radical species. To further explore the possible photolysis mechanism, we selected cisPt(IV)−1 as a model compound and monitored its photolysis by NMR spectroscopy. The predominant formation of acetic acid was confirmed by ¹H and ¹³C NMR (Supplementary Fig. 32), which was also evidenced by the decreasing pH upon irradiation (Supplementary Fig. 33). Two widely used radical spin traps, 5,5-dimethyl−1-pyrroline N-oxide (DMPO) and (2,2,6,6-tetramethylpiperidine−1-yl)oxyl (TEMPO)^33,34, were then used to trap the radical intermediates generated in the photolysis. Following irradiation for 10 min, different new species were observed in the presence of the radical spin traps (Fig. 2b and Supplementary Fig. 34a). On the contrary, the radical spin traps themselves were stable upon irradiation, and free cisPt(IV)−1 as well as its mixture with radical spin traps remained intact in the dark for up to 30 min (Supplementary Fig. 34b–f), showing that the radical species were formed as a result of the photolysis of cisPt(IV)−1. Notably, a new peak at 8.9 min appeared in the HPLC chromatogram from the mixture of DMPO and cisPt(IV)−1 upon irradiation, which was subsequently separated and characterized as the spin adduct of DMPO with acetato ligand (DMPO-Ac), evidencing the formation of acetate radicals (Fig. 2b and Supplementary Fig. 35)³⁵. The generation of CO₂ in the photolysis of cisPt(IV)−1 was confirmed by GC-MS (Supplementary Fig. 36), suggesting acetate radicals could transform into methyl radicals upon the release of CO₂. Furthermore, the platinum-containing spin adducts of TEMPO were identified by platinum’s characteristic isotopic pattern via ESI-HRMS^36,37. Two spin adducts of TEMPO with platinum, namely [Pt(NH₃)₂(TEMPO)Cl] and [Pt(NH₃)₂(TEMPO)OH], were observed in the solution of cisPt(IV)−1 upon irradiation, indicating the formation of Pt(I) radicals (Supplementary Fig. 37)³⁶. These spin-adduct products could not be observed in the Pt(II)-treated groups (Supplementary Figs. 35 and 37), indicating that these radical species originated directly from the photolysis of Pt(IV) complexes.

**Fig. 2: Mechanistic studies on the photolysis process of Pt(IV) prodrugs.**

To gain more insight into these reactive radical species, we subsequently performed electron paramagnetic resonance (EPR) measurements using DMPO and (2,2,6,6-tetramethylpiperidine)oxyl (TEMP) as the radical spin traps. As shown in Fig. 2c, a seven-line EPR spectrum of DMPOX, which was identified as the oxidized derivative of DMPO by chlorine radicals, appeared in the cisPt(IV)-1-treated group upon irradiation, suggesting the presence of chlorine radicals during the photolysis process. The N,N-diethyl-p-phenylenediamine (DPD) standard method was subsequently used to verify the formation of chlorine radicals^32,38. An absorbance spectrum peak at 515 nm, corresponding to Würster dye, a magenta-colored compound formed by the reaction between colorless DPD and free chlorine, was observed in the cisPt(IV)-1-treated group upon irradiation, but not the cisplatin-treated group (Supplementary Fig. 38a), confirming the production of chlorine radicals following the photolysis of the Pt(IV) species. A three-line signal, corresponding to TEMP adducts with singlet oxygen (TEMPO), disappeared in the solution of cisPt(IV)−1 upon irradiation (Supplementary Fig. 39a), further suggesting the production of radical species during the photolysis of the Pt(IV) prodrug, as radical species quench TEMPO^36,39. Similarly, distinctive EPR signals were also observed in samples treated with carPt(IV) (Supplementary Fig. 39b) and oxaPt(IV) (Supplementary Fig. 39c) upon irradiation. These signals indicated the formation of hydroxyl and carbon-centered radicals in the photolysis of carPt(IV) and oxaPt(IV), respectively^40,41, implying that the photolysis of Pt(IV) complexes typically results in radical generation.

Serendipitously, in a saturated cisPt(IV)−1 solution in water containing DMPO, a yellow precipitate was visually observed following irradiation, which was determined to be cisplatin using ESI-HRMS and proton NMR (Supplementary Fig. 40). We postulated that the radical spin trap might increase the yield of cisplatin and subsequently result in precipitation, due to the limited solubility of cisplatin in water. Consequently, the yield of cisplatin upon photolysis of cisPt(IV)−1 was monitored by LC-HRMS with and without DMPO or TEMPO. We found that the presence of these radical spin traps increased the yield of cisplatin in a concentration-dependent manner (Fig. 2d and Supplementary Figs. 41, and 42), and no significant difference in photolysis rates was observed following the addition of the radical spin traps (Fig. 2e and Supplementary Fig. 43). Based on these observations, we postulated that cisplatin is one of the photolysis products of cisPt(IV)−1, which is attacked by the reactive radical species generated during the photolysis process. In the presence of radical spin traps, these radical species are quenched, thereby resulting in a higher yield of cisplatin.

Given the observation that cisPt(IV)−1 generated reactive radical species during photolysis, we hypothesized that reactive oxygen species (ROS) could be further generated in the presence of oxygen and water. To corroborate this hypothesis, 2’,7’-dichlorofluorescein diacetate (DCFH-DA) was used as a ROS probe⁴². Compared with the samples treated with cisplatin, the solution of cisPt(IV)−1 exhibited significantly increased fluorescence intensity upon irradiation (Fig. 2f), suggesting the formation of ROS following the photolysis of cisPt(IV)−1. These results were further confirmed by using two colorimetric hydroxyl radical probes, 3,5,3’,5’-tetramethylbenzidine (TMB) and o-phenylenediamine (OPD)⁴³. Characteristic absorption peaks at 652 nm and 440 nm, of which are the oxidation products of TMB (oxTMB) (Supplementary Fig. 38b) and OPD (oxOPD) (Supplementary Fig. 38c) by hydroxyl radicals, respectively, were observed in the cisPt(IV)−1 but not the cisplatin-treated group upon irradiation. It should be noted that under hypoxia, less ROS was generated than that under normoxic conditions, as reflected in a decreased fluorescence intensity of DCF (Supplementary Fig. 44a), and different patterns of photolysis products were observed (Supplementary Fig. 44b), suggesting that oxygen is indeed involved in the photolysis process of cisPt(IV)−1 and generating ROS. In addition, HRMS revealed numerous identical new platinum species resulting from both the photolysis of cisPt(IV)−1 and the Fenton reaction with cisplatin (Supplementary Fig. 45), suggesting the generated ROS could further react with cisplatin, contributing to the complexity of the photolysis of cisPt(IV)−1.

Proposed photolysis mechanism

Collectively, based on the pieces of evidence described above, we propose a possible primary photolysis mechanism for cisPt(IV)−1 (Fig. 2g). Upon irradiation, cisPt(IV)−1 is excited to the singlet excited state, most probably to the S₅ state with relatively high oscillator strength that lies 362 nm above S₀, which was estimated by time dependent-density functional theory (TD-DFT) calculation (Supplementary Table 1). The calculated S₀-S₅ transition absorption falls within the range of wavelengths for light absorption of cisPt(IV)−1 observed by UV-Vis spectroscopy (Supplementary Fig. 46). Following excitation, rapid internal conversion processes may lead to the relaxation of the excited electrons to the S₁ state. The S₀-S₅ transition involves mostly charge transfer from the acetato ligands to the Pt(IV) equatorial core (Supplementary Fig. 47). The presence of platinum with strong spin-orbit coupling could also facilitate efficient intersystem crossing (ISC) from the singlet excited states to the lower-energy triplet excited states⁴⁴. These processes offer alternative pathways for the reaction to proceed, contributing to the complexity of the photolysis reaction. Subsequently, each acetato ligand transfers one electron to the Pt(IV) center (ligand to metal charge transfer, LMCT), resulting in homolytic cleavage of the Pt-O bond and subsequent reductive elimination, yielding cisplatin and acetate radicals⁴⁵. The relative potential energies in the reaction process were also examined by density functional theory (DFT) calculations (Supplementary Fig. 48 and Table 2). ΔE is −36.8 kcal/mol for the conversion of excited cisPt(IV)−1 to cisplatin and acetate radicals, suggesting that the reaction is thermodynamically favorable²⁴. The generated acetate radicals could either be rapidly quenched in the aqueous environment or decompose to CO₂, forming methyl radicals. These reactive radical species in the system attack cisplatin to yield chlorine radicals and various active platinum species, including the Pt(I) radicals. In the presence of oxygen and water, ROS could be further generated.

Currently, the applications of the photochemical properties of Pt(IV) prodrugs are limited to the release of cytotoxic Pt(II) species under irradiation for chemotherapy. Our study has revealed the unique photochemical properties of Pt(IV) prodrugs and highlights the differences in the properties of Pt(II) and Pt(IV) species. Therefore, broader applications of Pt(IV) coordination complexes can now be explored.

Pt(IV) prodrugs as photoinitiators for hydrogelation

Hydrogels are widely used in various biomedical settings, such as in flexible electronics, biosensors, and wound dressings, owing to their flexibility and moisture-retaining nature⁴⁶. For these applications, hydrogelation via photocrosslinking, antibacterial activities, and electrical conductive properties are highly desired, while it remains a great challenge to integrate multiple functions into one gel simultaneously, and complicated fabrication procedures are usually required^47,48,49. Given the generation of radical species during the photolysis of Pt(IV) complexes, we envisioned that these radical species could potentially initiate the polymerization of monomers to form a macromolecular hydrogel network (Fig. 3a). As a proof of concept, we first carried out a gelation experiment with acrylamide to examine the potential of Pt(IV) complexes as photoinitiators. Gratifyingly, the liquid solution was transformed into a solid-like gel upon irradiation in the sample treated with cisPt(IV)−1 but not cisplatin (Fig. 3b and Supplementary Fig. 49). To monitor the gelling process, a dynamic time-sweep rheological experiment was conducted in situ using a photo-rheometer. The exposure to UV light resulted in a significant increase in both storage modulus (G’) and loss modulus (G”), with G’ notably surpassing G”, signifying the successful formation of the hydrogel (Fig. 3c). A porous network and a homogeneous microstructure were observed using scanning electron microscopy (SEM; Fig. 3d). Next, we examined the mechanical properties of the resultant Pt-polyacrylamide (PAM) hydrogel through tensile testing. An initial increase in Young’s modulus of Pt-PAM hydrogel was observed with an increasing concentration of cisPt(IV)−1, followed by a decline (Supplementary Fig. 50). This pattern aligns with the typical behaviors of radical initiators. The Pt-PAM hydrogel demonstrated comparable mechanical properties to those initiated by the conventional photoinitiator I2959 (Fig. 3e), suggesting that Pt(IV) complexes function as effective alternative photoinitiators in the hydrogelation. To further examine the homogeneity of this Pt-PAM hydrogel, gel electrophoresis of specific protein markers, cell lysate, and bovine serum albumin was subsequently carried out using the Pt-PAM hydrogel. Similar to conventional APS/TEMED-gel (Supplementary Fig. 51), the protein samples separated well in the Pt-PAM hydrogel (Fig. 3f), suggesting the homogeneity of the Pt-PAM hydrogel. Collectively, these results confirm the ability of Pt(IV) complexes to act as versatile photoinitiators to induce photopolymerization of polymers, particularly in the context of hydrogel formation.

Antibacterial activity of the Pt-PAM hydrogel

Owing to the nature of high-water content, hydrogels are commonly susceptible to pathogen colonization, limiting their biomedical applications⁴⁸. The antibacterial activity of platinum complexes was discovered over half a century ago. Low concentrations of cisplatin can inhibit cell division and induce filamentous growth in E. coli⁵⁰. Noble metal nanoparticles, such as platinum nanoparticles, have also been incorporated into hydrogels to impart antibacterial activities^51,52. This unique property makes platinum a promising antibacterial agent for overcoming antibacterial resistance⁵³. Considering that Pt(IV) prodrugs act as photoinitiators in the gel formation process, and that, after the formation of the Pt-PAM hydrogel, the platinum may remain in the gel. It is possible that such Pt-PAM hydrogel may also exhibit antibacterial activity. Energy-dispersive spectroscopy (EDS) elemental mapping revealed the uniform distribution of platinum species within the Pt-PAM hydrogel matrix (Supplementary Fig. 52), comprising 85.4% Pt(II) and 14.6% Pt(IV) species, as measured by X-ray photoelectron spectroscopy (XPS, Supplementary Fig. 53a), and a substantial portion of the Pt(II) species was in the form of hydrated cisplatin (Supplementary Fig. 54). We then monitored the release profile of platinum from the Pt-PAM hydrogel scaffold; over 70% of the photolyzed platinum species were trapped in the Pt-PAM hydrogel network (Supplementary Fig. 55). The antibacterial performance of the Pt-PAM hydrogel was subsequently evaluated against E. coli (DH5α), a typical pathogenic Gram-negative bacteria, using the spread plate method⁵⁴. Control experiments using PBS, cisplatin, and a photocrosslinked gel prepared utilizing I2959, a widely-applied photoinitiator, were carried out concurrently^49,55. Many colonies of bacteria could be observed on the agar plates treated with PBS and the I2959-PAM hydrogel. In stark contrast, there were no visible colony-forming units (CFUs) on the agar plates treated with Pt-PAM hydrogel after 4 h (Fig. 3g). To further confirm the antibacterial activity of the Pt-PAM hydrogel, E. coli was incubated with or without the Pt-PAM hydrogel in lysogeny broth (LB), and the optical densities were measured at different time points. In the absence of the Pt-PAM hydrogel, the OD₆₀₀ values increased over time and remained stable after 10 h, consistent with the growth pattern of normal bacteria. In contrast, the OD₆₀₀ values remained low and unchanged in the Pt-PAM hydrogel-treated sample (Fig. 3h). As DNA is the primary target of platinum drugs, we subsequently assessed the binding of platinum to genomic DNA in E. coli. After incubation for 24 h, the Pt-PAM hydrogel exhibited a binding level of 2.2 ng Pt/μg DNA, notably lower than the binding observed with an equivalent concentration of free cisplatin (Supplementary Fig. 56). The morphology of bacterial cells after the treatment was further analyzed by SEM (Supplementary Fig. 57). Unlike the typical rod shape with a smooth surface observed in the control and I2959-PAM hydrogel-treated group, the bacterial show irregular shapes, with some appearing damaged or lysed, and a tendency to clump together, indicating the Pt-PAM gel’s efficacy in compromising the structural integrity of E. coli. Distinctive from that with the treatment of cisplatin, which typically induces filamentous growth through DNA damage, the cell wall disruption may also contribute to the antibacterial activity of Pt-PAM hydrogel.

Electrical and sensing performances of the Pt-PAM hydrogel

The incorporation of conductive polymers, metal nanoparticles, and free ions into hydrogels has been widely employed to achieve electrical properties⁵⁶. The photolysis products of cisPt(IV)−1 in the gel matrix might contain various mobile ions, including acetate anions, chlorine anions, and platinum cations; therefore, we envisioned that when an electric field is applied, these ions may act as charge carriers to transport charges throughout the hydrogel network, endowing the Pt-PAM hydrogel with electrical conductivity properties. As a proof of concept, a simple circuit was built to demonstrate the conductivity of the Pt-PAM hydrogel (Fig. 4a). With a direct current (DC) supply of 10 V, the light-emitting diode (LED) was lit up immediately upon connection with the Pt-PAM hydrogel (Fig. 4b), which was significantly brighter than that of the I2959-PAM hydrogel (Supplementary Fig. 58a), indicating the excellent conductivity of the Pt-PAM hydrogel. To investigate the role of the platinum complex in the conductivity of the Pt-PAM hydrogel, we tested the current in the circuit that was connected with the Pt-PAM hydrogel, which was prepared using different concentrations of cisPt(IV)−1. The current increased in the presence of platinum in a concentration-dependent manner (Supplementary Fig. 58b), which is significantly higher than that of the I2959-PAM gel, confirming that the conductivity was mainly derived from the introduction of platinum complexes and that the tunable electrical properties of the Pt-PAM hydrogel were from platinum. Notably, the LED turned dimmer distinctly when the Pt-PAM hydrogel was being stretched (Supplementary Fig. 58c), suggesting that the Pt-PAM hydrogel had a high strain sensitivity and could be a promising material for strain sensors. Consequently, the relative resistance change at different strains was evaluated. The Pt-PAM hydrogel presented a high sensing sensitivity at a broad strain range (0–666%), where the resistance increased significantly under stretching (Fig. 4c). The gauge factor, which characterized the strain sensitivity of sensors, increased from 5.2 to as high as 22.6, indicating excellent sensing sensitivity compared with other reported hydrogel-based sensors (Fig. 4c)⁵⁷.

The limited sensitivity of current ionic hydrogels stems from their inherently soft chain networks, which maintain strain-independent conductivity and cannot modulate ion transport during elongation. Consequently, resistance increases upon stretching are primarily attributed to changes in shape, following R/R₀ = λ² ⁵⁸. Indeed, for a typical ionic hydrogel, such as those containing LiCl as the ionic species (LiCl-PAM), the relative resistance changes are primarily shape-dependent and remain within a narrow range (R/R₀ = λ², Fig. 4c)⁵⁹. In contrast, the Pt-PAM hydrogel exhibited superior strain sensitivity, likely due to transient hydrogen bonding between mobile ions and the polymer backbone within the gel matrix. Specifically, the oxygen in acetate anions and the proton in platinum cations served as hydrogen bond acceptors and donors, respectively, interacting with amide groups in the polymer chains when in close proximity (Fig. 4d). DFT calculations modeled these interactions among acrylamide monomers, acetate anions, and platinum cations, revealing respective interaction energies of − 22.4, − 16.2 and − 18.1 kcal/mol (Supplementary Fig. 59). The distribution of ions within the gel matrix was homogeneous before deformation, which has an inherently soft chain network enabling efficient ion transport pathways. Upon stretching, the cross-sectional area decreased, leading to tighter packing of polymer chains, evidenced by reduced pore size in the stretched state (Supplementary Fig. 60). This closer arrangement increased interactions between mobile ions and polymer chains and consequently lowered their mobility (Fig. 4d). The rise in bulk resistance under stretching was thus not only due to shape change but also from the decreased conductivity, ultimately enhancing sensitivity (Fig. 4c). Similar to how narrowing roads forces cars to slow down and change lanes⁵⁹, an increase in ionic species within transport channels induced a more substantial “road-narrowing” effect, boosting ionic conductivity shift and enhanced strain sensitivity (Supplementary Fig. 61a). This effect is pronounced in Pt-PAM hydrogel, as the strain sensitivity increased with rising concentrations of cisPt(IV)−1 (Supplementary Fig. 61b), owing to the ion-polymer interactions, where ionic species are captured by polymer chains when in close proximity, slowing their movement (Fig. 4d). In contrast, the conventional LiCl-PAM hydrogel exhibited little variation in sensitivity with increasing ionic concentration (Supplementary Fig. 61c), despite both types of hydrogels exhibiting higher current with increasing concentrations of ionic species (Supplementary Fig. 62). A similar trend was observed with a hydrogel prepared using hydrated cisplatin and 2 equiv. of acetic acid (Supplementary Fig. 61d), suggesting that the behavior observed was not attributable to changes in crosslinking density resulting from varying concentrations of cisPt(IV)−1 as the photoinitiator.

We subsequently evaluated the performance of the Pt-PAM hydrogel under different repeated deformation modes. Upon being repeatedly stretched (Fig. 4e), pressed (Fig. 4f), and twisted (Fig. 4g), distinct yet stable signal outputs of the changes of resistance were generated from the Pt-PAM hydrogel, demonstrating the excellent sensitivity and reliability of the Pt-PAM hydrogel as a strain sensor. In addition, Pt-PAM hydrogels exhibited robust adhesion against various substrates, including glass, rubber, steel, and plastic (Fig. 4h), which is crucial for applications like wearable sensors, medical adhesives, and soft robotics that demand secure attachment and effective interface with surfaces. The adhesive strength of the Pt-PAM hydrogel is significantly higher than the I2959-PAM hydrogel by lap-shear tests with glass (Fig. 4i and Supplementary Fig. 63a, b), likely owing to the additional coordination bonding and electrostatic interactions by the introduction of platinum species (Supplementary Fig. 63c). Encouraged by these results, we further examined the potential of the Pt-PAM hydrogel as a wearable sensor to monitor various real-time human motions. As depicted in Fig. 4j, the Pt-PAM hydrogel was affixed at the finger joint to monitor its movement. Sequentially bending the finger at different angles results in corresponding increases in the relative resistance of the Pt-PAM hydrogel. The electrical signals demonstrated high repeatability and stability. Similarly, when applying the Pt-PAM hydrogel to the elbow (Fig. 4k), wrist (Fig. 4l), and knee (Supplementary Fig. 58d), distinct signals could be observed, and the Pt-PAM hydrogel could clearly sense the bending amplitude of the elbow and the bending direction of the wrist.

Protein photocrosslinking of Pt(IV) prodrugs

As electrophiles, Pt(II) complexes have been applied as protein crosslinkers in antibody-drug conjugates^60,61. We reasoned that the unique photoinduced reactive Pt species, including the platinum radicals and Pt(II) species generated from classical Pt(IV) prodrugs, could potentially react with various biological nucleophiles, and thus, Pt(IV) prodrugs could be considered as photocaged electrophiles. As a proof of concept, we first examined the reactivity of Pt(IV) prodrugs with individual model amino acids upon photolysis. Indeed, Pt-amino acid adducts were observed using ESI-HRMS (Supplementary Fig. 64). To translate these observations to actual protein crosslinking reactions, we next examined the binding efficiency with bovine serum albumin (BSA) using ICP-OES. Without irradiation, both Pt(II) and Pt(IV) species displayed a limited ability to bind protein; less than 10% of platinum complexes bound to the BSA, and the Pt(IV) complexes exhibited a slightly lower binding ratio than the Pt(II) counterparts due to their greater kinetic inertness¹⁰. In contrast, following irradiation, a significant increase in binding ratio was observed in the Pt(IV)-treated samples. For cisPt(IV)−1 and carPt(IV), over 80% of the platinum complexes bound to BSA, indicating that the photolyzed platinum products could crosslink to the protein efficiently (Supplementary Fig. 65). The observed increase in the m/z values by MALDI-TOF in the BSA samples treated with cisPt(IV)−1 demonstrates the covalent linking nature in the formation of protein-Pt adducts. This covalent binding characteristic was similarly noted in other model proteins including cytochrome c, myoglobin, and ribonuclease A, suggesting the broad applicability of Pt(IV) complexes as photocrosslinkers across various proteins (Supplementary Fig. 66). It is worth noting that the presence of a high level of cisPt(IV)−1 induces changes in the secondary structure of BSA, as indicated by the altered spectra in CD spectroscopy (Supplementary Fig. 67).

Pt(IV) prodrugs as photocrosslinkers for hydrogelation of gelatin

Gelatin, a mixture of proteins and peptides derived from animal skin, has wide biomedical applications in tissue engineering and wound dressing⁴⁶. Conventionally, to achieve photocrosslinking, gelatin is first functionalized with methacrylamide, a crosslinker; in the presence of a photoinitiator such as I2959, the modified peptides crosslink immediately upon irradiation to form a hydrogel⁵⁵. Gelatin is known to comprise 6–7% of aspartic acid (Asp) and 10−12% of glutamic acid (Glu). Given the observation of the crosslinking products with two glutamic acids (Supplementary Fig. 64) and the efficient protein photocrosslinking properties of the Pt(IV) complexes (Supplementary Fig. 65), we envisioned that the Pt(IV) species might act as photocrosslinkers to directly produce a gelatin hydrogel without the need for functionalization first and then a photoinitiator (Fig. 5a). As a proof of concept, we performed gelation experiments using cisplatin and cisPt(IV)−1. Upon irradiation, the formation of gelatin hydrogel could be clearly observed in the cisPt(IV)−1-treated sample but not the cisplatin-treated one (Fig. 5b). The successful hydrogelation was confirmed in rheological measurements with the storage modulus (G’) consistently exceeding loss modulus (G”), which are also significantly higher than those with gelatin solution (Fig. 5c). To gain a deeper insight into the Pt-gelatin hydrogel, we employed EDS mapping to reveal the uniform distribution of platinum species in the Pt-gelatin hydrogel matrix (Supplementary Fig. 68), predominantly as Pt(II) species, which was evidenced by the XPS analysis (Supplementary Fig. 53b). Thermal gravimetric analysis (TGA) revealed increased thermal stability of Pt-gelatin hydrogel with higher concentrations of cisPt(IV)−1 (Fig. 5d), indicating the higher crosslinking density endowed by the platinum. Additional signals could be observed in the region around 500 cm⁻¹ in the Raman spectra (Fig. 5e), which could be attributed to the stretching of platinum-oxygen bonding⁶², pointing to interactions between platinum and the carboxylate side chains of Asp and Glu within the gelatin peptide chains. Collectively, these results suggest that Pt(IV) complexes can be used as photocrosslinkers for the direct fabrication of gelatin hydrogel scaffolds.

**Fig. 5: Pt(IV) prodrugs as photocrosslinkers for hydrogelation and protein labeling.**

Pt(IV) prodrugs as photocrosslinkers for protein labeling

The majority of current photoreactive protein labeling reagents involve carbene-enabled C-H and N-H insertion chemistry, which suffers from low crosslinking efficiency due to the short-ranged carbene species⁶³. Encouraged by these results, we further designed and synthesized a metal-based photocrosslinker alkyne-Pt(IV) (Fig. 5f and Supplementary Figs. 69–74), which is based on cisPt(IV)−1 and contains a bioorthogonal handle alkyne⁶⁴. Upon photolysis, the reactive platinum species could crosslink to proteins instantly, allowing the subsequent introduction of reporters, such as fluorescence groups, via click chemistry (Fig. 5f). The labeling efficiency of alkyne-Pt(IV) was subsequently evaluated using BSA. Popular benzophenol- and diazirine-based photocrosslinkers, PC−1 and PC-2, were synthesized and included for comparison (Supplementary Figs. 69 and 75–81)⁶⁵. We also synthesized a Pt(II) counterpart, alkyne-Pt(II), as a control (Supplementary Figs. 69 and 82–86). Without irradiation, all probes exhibited low labeling efficiency, with alkyne-Pt(II) exhibiting a relatively higher labeling efficiency than alkyne-Pt(IV). In stark contrast, under irradiation, a significant enhancement in fluorescence was observed in the sample treated with alkyne-Pt(IV). The fluorescence intensity from alkyne-Pt(IV) was 1.7-fold higher than those of the organic probes PC−1 and PC-2 (Fig. 5g, h), indicating its great protein labeling efficiency. No change in protein mobility was observed in the native polyacrylamide gel (Supplementary Fig. 87), suggesting that the BSA structure remained intact under this conditions. Furthermore, to examine the kinetics of the photocrosslinking process, pulse-chase labeling of proteins was carried out by switching the light on and off. The light dependence of protein labeling was observed, with distinct increases in the fluorescence intensity following each pulse of light, indicating the instant nature of the crosslinking process and the temporal specificity afforded by the use of external light (Fig. 5i and Supplementary Fig. 88). It should be noted that alkyne-Pt(II) also exhibited modestly increased fluorescence upon irradiation, aligning with a slight enhancement in the percentage of platinum bound to BSA from the Pt(II) complexes under UV exposure (Supplementary Fig. 65). Together with the observation of enhanced hydrolysis from Pt(II) complexes upon UV irradiation (Supplementary Fig. 89), these results suggest the ligand photodissociation of Pt(II) complexes under UV exposure, thereby facilitating the protein binding.

Discussion

In summary, our study reports the photochemical properties of Pt(IV) complexes containing innocent axial ligands, derived from clinically used Pt drugs, demonstrating their potential for a broader range of biomedical applications. In contrast to their relative kinetic inertness in the dark, Pt(IV) complexes, rather than their Pt(II) counterparts, photolyzed rapidly upon exposure to UV light, producing various radical species. Specifically, upon irradiation, cisPt(IV)−1 generates reactive radical species, including platinum radicals, chlorine radicals, acetate radicals, and ROS.

With d⁶ configuration and electron-deficient nature, the investigated Pt(IV) complexes feature more empty d orbitals and additional sigma-donating carboxylate axial ligands, enhancing the likelihood of LMCT. Besides, the higher oxidation state of Pt(IV) increases the nuclear charge, lowering d orbital energy and narrowing the energy gap between ligand and metal orbitals. This shift causes LMCT absorption to move into the UVA region, as evidenced by stronger absorption of the investigated Pt(IV) complexes in the UVA region (Supplementary Fig. 29). The electron density transfer during LMCT alters oxidation states of ligands and the metal center, leading to unstable configurations and vulnerable bonds, and thus facilitating the formation of unpaired electrons and reactive species. Traditionally valued for their kinetic inertness and used as prodrugs, Pt(IV) complexes exhibit unique photochemical behaviors such as radical generation and protein photocrosslinking, underlying the photolytic condition, opening up avenues for diverse biomedical applications.

The integration of multiple functionalities into hydrogel matrices typically presents a significant challenge, necessitating complicated and multi-step fabrication processes. Our study demonstrates the successful hydrogelation with acrylamide using Pt(IV) complexes as innovative photoinitiators. More importantly, Pt(IV) complexes go beyond the conventional role of photoinitiators by not only initiating polymerization upon light exposure but also simultaneously empowering the resultant Pt-PAM hydrogel with the capabilities of photocrosslinking, antibacterial activities, adhesiveness, and superior electrical and sensing performance. By harnessing the unique properties of Pt(IV) complexes, we achieved these multifunctionalities within a single gel matrix in a facile and one-pot process, offering a simple strategy for the facile fabrication of multifunctional hydrogel. Significantly, the transient hydrogen bonding between the resultant mobile ions and the polymer chain rendered the Pt-PAM hydrogel with improved strain sensitivity, breaking the restrictions of conventional ionic hydrogels.

Conventionally, gelatin photocrosslinking involves initial functionalization with methacrylamide, followed by crosslinking upon irradiation in the presence of a photoinitiator. In our study, Pt(IV) complexes present an alternative approach, serving as effective photocrosslinkers for the direct fabrication of gelatin hydrogel scaffold without the need for such pre-functionalization. Furthermore, the current landscape of photoreactive protein labeling reagents mainly depends on organic carbene-mediated chemistry, limited by carbene’s short lifespan and low crosslinking efficiency. Our alkyne-Pt(IV) probe demonstrates the potential of Pt(IV) species as general photoreactive protein labeling reagents. With superior labeling efficiency, this Pt-based reagent opens up possibilities for more effective protein labeling techniques in the field of bioconjugation.

Collectively, our findings offer valuable insight into the behaviors of Pt(IV) coordination complexes, contributing to our current understanding in the field of platinum photochemistry underlying their photolytic conditions. The distinctive photolysis properties of Pt(IV) complexes, along with their potential as photoinitiators, photocrosslinkers, and photoreactive protein labeling reagents, point toward broader applications in research areas such as chemical biology, materials science, and biomedical engineering, going beyond their traditional role as antineoplastic agents.

Methods

The experiments for human motion sensing were performed in compliance with all the ethical regulations under a protocol that was reviewed and approved by the College Research Ethics Sub-Committee of City University of Hong Kong. As the study focused on demonstrating sensor functionality rather than biological variability, sex and gender analysis was not applicable.

Photolysis of Pt complexes

The photolysis of Pt complexes in test tubes was examined by reversed-phase high-performance liquid chromatography (RP-HPLC). 1 mM Pt complexes were dissolved in water. Then the mixed solution was irradiated with UV light (365 nm, 9.8 mW/cm²) for 10 min at room temperature, and the solution was examined by HPLC. The percentage of remaining Pt complexes was obtained from the ratio of the peak area of Pt complexes upon irradiation to that of the intact Pt complexes. The photolysis products were analyzed by LC-HRMS.

Radical spin trap assay

1 mM cisPt(IV)−1 and cisplatin in water were mixed with 1 or 10 mM DMPO or TEMPO. The mixed solution was irradiated with UV or kept in the dark for 10 min. The solution was analyzed by HPLC. The Pt(I) adduct products were characterized by ESI-HRMS, and the acetate radical adduct was separated and characterized by proton NMR. For the study of photolysis rate, the solution was irradiated with UV (365 nm, 9.8 mW/cm²) for 0.5, 1, 2, 3, 4, 5, and 10 min, with or without the radical spin trap, and analyzed by HPLC. For the study of dark stability, the solution was incubated at room temperature in the dark for 30 min before being examined by HPLC.

Electron paramagnetic resonance (EPR)

EPR spectra were recorded with an ADANI SpinscanX spectrometer, operating at 100 kHz field modulation using the 150 μT modulation amplitude. 5,5-dimethyl−1-pyrroline N-oxide (DMPO) and 2,2,6,6-tetramethylpiperidine (TEMP) were chosen as the spin traps. Typically, 500 mM DMPO or TEMP was mixed with 25 mM cisPt(IV)−1 in water. The mixture was then irradiated with UV or kept in the dark for 10 min at room temperature. The samples were transferred to a quartz capillary, and the EPR spectra were recorded at room temperature.

Reactive species detection by probes

Stock solutions (25 mM) of N,N-diethyl-p-phenylenediamine (DPD) (for the detection of chlorine radicals), methylene blue (MB) (for ROS, chlorine, and hydroxyl radicals), 2,3-diaminophenazine (OPD) (for ROS and hydroxyl radicals), 3,3’,5,5’-tetramethylbenzidine (TMB) (ROS, hydroxyl radicals) were prepared in DMF, while cisPt(IV)−1 (50 mM) stock was prepared in water. For testing, cisPt(IV)−1 and the probes were mixed and diluted to 500 μM of cisPt(IV)−1 and 250 μM of the probes in water. The mixtures were irradiated with UV (365 nm, 9.8 mW/cm²) for 10 min or kept in the dark. The absorbance of probes was recorded by the plate reader. The experiments with methylene blue were diluted five times before the reading.

Total ROS generation in solution detected by DCFH

20 μL of 2’,7’-dichlorodihydrofluorescein diacetate (DCFH-DA) (1 mM) was added to 80 μL of sodium hydroxide in water (10 mM) and stirred for 30 min at room temperature in the dark to obtain DCFH. Next, 400 μL of phosphate-buffered saline (pH 7.4) was added to the mixture to obtain a DCFH solution (40 μM). Then 5 μM DCFH was added to 50 μM Pt complexes in PBS buffer, followed by irradiation with UV (365 nm, 9.8 mW/cm²) for 10 min or kept in the dark. For the hypoxia experiment, the complex solution was deoxygenated by infusion of argon gas for 15 min. The fluorescence was monitored by the plate reader with the excitation at 450 nm, and emission at 490 to 700 nm.

Quantification of cisplatin by LC-HRMS

1 mM cisPt(IV)−1 was added to different concentrations (0, 0.1, 1, 10, 50/100 mM) of DMPO/TEMPO in water. The mixture was irradiated with UV light (365 nm, 9.8 mW/cm²) for 10 min at room temperature. After that, the solution was diluted 50 times before being analyzed by the LC-HRMS. For the hypoxia experiment, the complex solution was deoxygenated by infusion of argon gas for 15 min. The major ion intensity of cisplatin at 300.9608 was selected for quantification, and the concentration of cisplatin was quantified from the peak area of the standard curve.

DFT calculations

The geometry of the system was optimized using Gaussian 16 Rev. A.03 software based on density functional theory (DFT). The PBE0 functional is utilized with DFT-D3BJ dispersion correction. The 6–31 g* basis set is used for main group elements (H, N, C, Cl), and the Stuttgart pseudopotential basis set is used for the platinum element. The Shermo program is applied for the Gibbs free energy post-processing, and the free energy difference of the reaction is thus derived. The singlet excited states of the system were calculated by the TD-DFT method. The interaction energy was calculated from the equation: E_int= E_complex – E_D – E_A, where E_complex is the energy of the model complex system, and E_D and E_A are the energy of the individual hydrogen bond donor and acceptor, respectively.

Gelation assay

Hydrogelation experiments were carried out in glass vials. In a typical experiment, 100 μM of platinum complexes were added to 10% acrylamide/bis-acrylamide (29:1) in water. For hydrogelation with gelatin, 1 mM of platinum complexes was mixed with 5% gelatin in water. The mixture was irradiated with 365 nm light (9.8 mW/cm²) for 10 min at room temperature, and the formed hydrogel was tested by the vial inversion method.

For protein electrophoresis, 1 mM cisPt(IV)−1 was added to 10% acrylamide/bis-acrylamide (29:1), 375 mM Tris-HCl (pH 8.8), and 0.1% SDS in water. The mixture was irradiated at 365 nm (9.8 mW/cm²) for 10 min at room temperature to form the Pt-PAM hydrogel. Samples of 3 μL protein marker (Beyotime P0076), 5 μg BSA, and 20 μg A2780 cell lysate were loaded. After separation, the gels were stained with Coomassie blue and imaged by a ChemiDoc Touch imaging system.

Mechanical and Rheological tests

The mechanical properties of the Pt-PAM hydrogel were measured by a tensile tester (Instron 3382) equipped with a 1000 N load cell. The hydrogel samples were cut into a rectangular shape (40 mm × 30 mm x 2.5 mm) in advance. The tensile speed of 100 mm/min was applied at room temperature in the air. Rheological behaviors of the hydrogels were analyzed using a Thermo HAAKE MARS 60 rheometer, equipped with a parallel plate (diameter, 25 mm) through a small-amplitude oscillatory shear mode at 37 °C. Frequency sweeps were performed from 10 to 0.1 rad s⁻¹ at a strain amplitude of 0.2%. Time sweeps were conducted at a constant frequency of 1 Hz and a strain amplitude of 1%. UV irradiation was applied for durations ranging from 60 to 200 s.

Adhesion tests

The adhesion properties of Pt-PAM hydrogel were examined using the lap-shear test on a tensile tester (MTS CM6103) equipped with a 1000 N load cell. The hydrogel samples were cut into rectangular sheets (10 mm × 10 mm), and coated on one side of the substrate and overlapped with another substrate to form a sandwich structure. This assembly was then stretched at a rate of 10 mm/min. The adhesion strength was determined by dividing the maximum force representing the joint at the point of joint failure by the area of the hydrogel.

Antibacterial assay

100 μL hydrogel (0.1% I2959 or 1 mM cisPt(IV)−1 + 10% acrylamide/ bis-acrylamide (29:1) were prepared in a 96-well plate. The mixtures were irradiated (365 nm, 9.8 mW/cm²) for 20 min and washed with PBS twice. 20 μL of DH5α (around 9 × 10⁷ CFU/mL) in PBS was added to the surface of the gel. Controls were carried out with 100 μM cisplatin in PBS or pure PBS concurrently. After incubation for 4 h at 37 °C, the samples were washed with 100 μL PBS twice. The PBS were combined to collect the surviving bacteria and further diluted 10,000 times. 20 μL of bacteria in PBS were then evenly spread on the 10 cm agar plates and incubated for 18 h at 37 °C, before being imaged by a ChemiDoc Touch imaging system. The optical density OD₆₀₀ was also monitored every half an hour without or in the presence of Pt-PAM hydrogel treated with DH5α in LB medium with the microplate reader. Upon treatment for 12 h, the bacterial cells were collected and dehydrated with sequential ethanol (30%, 50%, 70%, 90%, and 100%). The dehydrated bacteria were imaged by SEM after being coated with gold. After treatment for 24 h, the bacteria were collected, and their DNA was purified with GeneJET Genomic DNA Purification Kit. The platinum content in the DNA was determined by ICP-MS after digestion with concentrated HNO₃ at 80 °C overnight. The same amount of cisplatin was included as a control.

Release profile of platinum in the Pt-PAM hydrogel

500 μL Pt-PAM hydrogel was prepared by mixing 10% acrylamide/ bis-acrylamide (29:1) and 1 mM cisPt(IV)−1 in water and irradiated with UV for 10 min in a 48-well plate. The Pt-PAM hydrogel was washed with 1 mL PBS and transferred to a 15 mL tube. 5 mL PBS or lysogeny broth was added, and the mixture was incubated at 37 °C with gentle shaking. 200 μL supernatant was taken at the given time points. The Pt concentration was ascertained by ICP-OES after digestion with concentrated HNO₃ at 80 °C overnight. The Pt species was characterized by LC-HRMS.

Electrical and sensing behaviors of the Pt-PAM hydrogel

Hydrogel samples were prepared using 25% acrylamide/ bis-acrylamide (1600:1) in deionized water under different conditions. I2959-PAM hydrogel was prepared by incorporating 0.1% I2959. Pt-PAM hydrogel was prepared by adding varying concentrations of cisPt(IV)−1. LiCl-PAM hydrogel was prepared with 0.1% I2959 and varying concentrations of LiCl. A hydrated cisplatin hydrogel was prepared with the incorporation of 0.5% I2959, various concentrations of hydrated cisplatin, and two equivalents of acetic acid. All mixtures were exposed to UV light for 10 min at room temperature. The measured hydrogels were cut into rectangular sheets with the following dimensions: thickness of 2 mm, width of 10 mm, and length of 30 mm. The electrical tests were conducted along the length of these sheets and connected with copper wires. The LED light was powered by a 10 V supply in the hydrogel connection circuit. The real-time resistance of the Pt-PAM hydrogel under different deformation and human motions was calculated according to the I-t curve that was recorded by an electrochemical workstation (CHI660C, CH Instruments, USA) at a constant voltage of 0.2 V and room temperature. The relative resistance change (ΔR/R₀) of the deformed hydrogel was calculated according to the following equation: ΔR/R₀ = R/R₀– 1 = (I₀/I – 1) × 100%, where I₀ and I were the pristine and real-time current in the circuit connected with the Pt-PAM hydrogel, respectively. The gauge factor (GF) was calculated according to GF = (ΔR/R₀)/ε, where ε is the corresponding strain applied during the test. The experiments for human motion sensing were performed in compliance with all the ethical regulations under a protocol that was reviewed and approved by the College Research Ethics Sub-Committee of City University of Hong Kong.

BSA binding

5 mg/mL BSA was mixed with Pt complexes (final Pt concentration = 50 μM) in PBS (pH 7.4) buffer. The mixture was incubated for an hour at 37 °C, prior to irradiation (365 nm, 9.8 mW/cm²) with UV or being kept in the dark for 10 min at room temperature. After that, acetone was added to the solution and kept at − 20 °C for an hour to precipitate. The protein pellet was collected by centrifugation (20,817 × g, 10 min at 4 °C) and resuspended in PBS buffer. The binding content of Pt was ascertained by ICP-OES after digestion with concentrated HNO₃ at 80 °C overnight.

In vitro BSA photolabeling

3 mg/mL BSA in PBS (pH 7.4) buffer was treated with different compounds at 10 μM (0.1% DMF). The mixture was incubated for 1 h at 37 °C prior to UV irradiation (365 nm, 9.8 mW/cm²) for 5 min at room temperature. The reaction was then quenched by the addition of acetone and stored at − 20 °C for an hour. The precipitated protein pellet was then collected by centrifugation (20,817 × g, 10 min at 4 °C). The samples were dissolved in PBS, followed by the addition of a freshly pre-mixed click chemistry reaction cocktail (100 μM TBTA, 1 mM CuSO₄, 1 mM TCEP, and 50 μM TAMRA-N₃). The reaction was incubated for an hour at ambient temperature before quenching with SDS-PAGE loading buffer. The labeled protein was separated by SDS-PAGE and visualized by in-gel fluorescence scanning.

For time-tracking analysis of the reaction, 3 mg/mL BSA in PBS was treated with Pt(IV)-based photo-crosslinker at 10 μM (0.1% DMF). A 50 μL aliquot was taken every two minutes and precipitated with acetone. At given time points (5, 11, and 17 min), the reaction mixture was irradiated with UV for 30 s. The precipitated protein pellets were dissolved in PBS and analyzed by in-gel fluorescence scanning as described above.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

All data supporting the findings of this study are available within the article and its Supplementary Information. All data underlying this study are available from the corresponding author upon request. Source data are provided in this paper.

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Acknowledgements

We thank the National Natural Science Foundation of China (Grant Nos. 22077108 and 22277103), the Hong Kong Research Grants Council (Grant Nos. CityU 11302221, CityU 11313222, CityU 11304923, CityU 11306724, and C1018-23G), and the Science Technology and Innovation Committee of Shenzhen Municipality (JCYJ20210324120004011) for funding support.

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Authors and Affiliations

Department of Chemistry, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
Jiaqian Xu, Qiyuan Zhou, Guohan Sun, Gongyuan Liu, Shu Chen, Zhao Yue, Ka-Yan Ng, Houzong Yao, Fu Shing Li, Yung-Kang Peng & Guangyu Zhu
City University of Hong Kong Shenzhen Research Institute, Shenzhen, People’s Republic of China
Jiaqian Xu, Qiyuan Zhou, Gongyuan Liu, Shu Chen, Zhao Yue, Ka-Yan Ng, Houzong Yao & Guangyu Zhu

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Jiaqian Xu
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Qiyuan Zhou
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Guohan Sun
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Gongyuan Liu
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Shu Chen
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Zhao Yue
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Ka-Yan Ng
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Houzong Yao
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Fu Shing Li
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Yung-Kang Peng
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Guangyu Zhu
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Contributions

J.X. and G.Z. designed the project. J.X. and Q.Z. performed the synthesis of the compounds; G.S. and Y.-K.P. performed the EPR test; G.L., S.C., Z.Y., H.Y., K.-Y.N., and F.S.L. contributed to the manuscript preparation.

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Correspondence to Guangyu Zhu.

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Competing interests

J.X. and G.Z. are inventors on U.S. patent application no. US 2024/0400596 A1 and Chinese patent application no. CN119060097A submitted by the City University of Hong Kong, which covers the design, synthesis, and applications of the Pt(IV) complexes as photoinitiators and photocrosslinkers for hydrogelation and protein labeling. The other authors declare that they have no competing interests.

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Xu, J., Zhou, Q., Sun, G. et al. Harnessing platinum(IV) prodrugs as versatile photoinitiators and photocrosslinkers for multifunctional hydrogels and protein labeling. Nat Commun 16, 8879 (2025). https://doi.org/10.1038/s41467-025-63958-2

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Received: 26 September 2023
Accepted: 02 September 2025
Published: 06 October 2025
Version of record: 06 October 2025
DOI: https://doi.org/10.1038/s41467-025-63958-2