Abstract
In the development of clinically translatable triplet photosensitizers for hypoxia regulated photodynamic therapy (PDT), there is an unmet need for engineering sensitizers as near-infrared (NIR)-responsive, type I/type Ⅱ dual photosensitizers and mild photothermal agents. Herein, we develop a binary precursor-engineering strategy for precise regulation of the D-π-A configuration of carbon dots (CDs) as ultralong-lived triplet, type I/Ⅱ dual photosensitizers by utilizing phenolic hydroxyl as an electron-rich donor and pyridine N as an electron-withdrawing acceptor. The photodynamic performance of CDs is enhanced by intramolecular charge transfer and mild photothermal conversion. We further design M1-like macrophage-derived cell membrane‑camouflaged CDs to realize preferential tumor accumulation while guaranteeing rapid systemic clearance. D-π-A sensitized CD-mediated PDT induces anti-tumor activity against primary and distant tumors. Our work highlights the crucial roles of D-π-A sensitization of CDs in boosting PDT by triplet state tuning, surface charge transfer, and mild photothermal relief of hypoxia.
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The authors declare that all relevant data supporting the findings of this study are available within the article, its Supplementary Information, and Source data. Source data are provided with this paper.
References
Li, J. et al. Off-photosensitizing derived immuno-photodynamic therapy toward postoperative care. Adv. Funct. Mater. 35, 2419598 (2024).
Lucky, S. S., Soo, K. C. & Zhang, Y. Nanoparticles in photodynamic therapy. Chem. Rev. 115, 1990–2042 (2015).
Li, X., Lovell, J. F., Yoon, J. & Chen, X. Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat. Rev. Clin. Oncol. 17, 657–674 (2020).
Jiang, Y., Li, J., Zhen, X., Xie, C. & Pu, K. Dual-peak absorbing semiconducting copolymer nanoparticles for first and second near-infrared window photothermal therapy: a comparative study. Adv. Mater. 30, 1705980 (2018).
Yi, X. et al. Bacteria-triggered tumor-specific thrombosis to enable potent photothermal immunotherapy of cancer. Sci. Adv. 6, eaba3546 (2020).
Huang, L. et al. Mild photothermal therapy potentiates anti-PD-L1 treatment for immunologically cold tumors via an all-in-one and all-in-control strategy. Nat. Commun. 10, 4871 (2019).
Nam, J. et al. Cancer nanomedicine for combination cancer immunotherapy. Nat. Rev. Mater. 4, 398–414 (2019).
Shao, Y. et al. Engineering of upconverted metal-organic frameworks for near-infrared light-triggered combinational photodynamic/chemo-/immunotherapy against hypoxic tumors. J. Am. Chem. Soc. 142, 3939–3946 (2020).
He, C. et al. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat. Commun. 7, 12499 (2016).
Wei, Q., Liu, S., Huang, X., Xin, H. & Ding, J. Immunologically effective biomaterials-enhanced vaccines against infection of pathogenic microorganisms. Biosaf. Health 5, 45–61 (2023).
Guo, Y. et al. Magnetic-responsive and targeted cancer nanotheranostics by PA/MR bimodal imaging-guided photothermally triggered immunotherapy. Biomaterials 219, 119370 (2019).
Li, J. et al. Second near-infrared photothermal semiconducting polymer nanoadjuvant for enhanced cancer immunotherapy. Adv. Mater. 33, 2003458 (2021).
Zheng, R. R. et al. Paraptosis inducer to effectively trigger immunogenic cell death for metastatic tumor immunotherapy with IDO inhibition. ACS Nano 17, 9972–9986 (2023).
Li, X. et al. A diketopyrrolopyrrole-based all-in-one nanoplatform for self-reinforcing mild photothermal therapy cascade immunotherapy for tumors. Adv. Healthc. Mater. 13, 2400766 (2024).
Liu, T. et al. Rhythmic mild photothermal therapy enhancing anti-PD-L1 response for oral squamous cell carcinoma immunotherapy. Chem. Eng. J. 488, 150908 (2024).
Wang, M. et al. A noble AuPtAg-GOx nanozyme for synergistic tumor immunotherapy induced by starvation therapy-augmented mild photothermal therapy. Adv. Sci. 9, 2202332 (2022).
Liu, C. et al. NIR-triggered dual sensitization of nanoparticles for mild tumor phototherapy. Nano Today 42, 101363 (2022).
Sun, J. et al. Multi-bioactive poly(amino acid)-metal-organic framework nanocomposite for reinforced cascading photodynamic immunotherapy of cancer. Biomaterials 324, 123488 (2025).
Kang, X. et al. A photo-triggered self-accelerated nanoplatform for multifunctional image-guided combination cancer immunotherapy. Nat. Commun. 14, 5216 (2023).
Luo, T. et al. Nanoscale metal-organic frameworks stabilize bacteriochlorins for type I and type II photodynamic therapy. J. Am. Chem. Soc. 142, 7334–7339 (2020).
Shi, Z. et al. Engineering structural metal–organic framework for hypoxia-tolerant type I photodynamic therapy against hypoxic cancer. ACS Mater. Lett. 3, 781–789 (2021).
Deng, Y. et al. 3-Bromopyruvate-conjugated nanoplatform-induced pro-death autophagy for enhanced photodynamic therapy against hypoxic tumor. ACS Nano 14, 9711–9727 (2020).
Chen, D. et al. A highly-efficient type I photosensitizer with robust vascular-disruption activity for hypoxic-and-metastatic tumor specific photodynamic therapy. Small 16, 2001059 (2020).
Yuan, Z. et al. Near-infrared light-triggered nitric-oxide-enhanced photodynamic therapy and low-temperature photothermal therapy for biofilm elimination. ACS Nano 14, 3546–3562 (2020).
Wen, K. et al. Achieving efficient NIR-II Type-I photosensitizers for photodynamic/photothermal therapy upon regulating chalcogen elements. Adv. Mater. 34, 2108146 (2022).
Wen, K. et al. Precisely tuning photothermal and photodynamic effects of polymeric nanoparticles by controlled copolymerization. Angew. Chem. Int. Ed. 59, 12756–12761 (2020).
Wang, Y. et al. Atomic-level nanorings (A-NRs) therapeutic agent for photoacoustic imaging and photothermal/photodynamic therapy of cancer. J. Am. Chem. Soc. 142, 1735–1739 (2020).
Chuang, C.-C. et al. Stem cell-based delivery of Gold/Chlorin e6 nanocomplexes for combined photothermal and photodynamic therapy. ACS Appl. Mater. Interfaces 12, 30021–30030 (2020).
Chen, W. et al. Black phosphorus nanosheet-based drug delivery system for synergistic photodynamic/photothermal/chemotherapy of cancer. Adv. Mater. 29, 1603864 (2017).
Chang, X. et al. Enhanced manipulation of tumor microenvironments by nanomotor for synergistic therapy of malignant tumor. Biomaterials 290, 121853 (2022).
Zhang, L. et al. Intelligent gold nanostars for in vivo CT imaging and catalase-enhanced synergistic photodynamic & photothermal tumor therapy. Theranostics 9, 5424–5442 (2019).
Yu, Y. et al. Bortezomib-encapsulated cus/carbon dot nanocomposites for enhanced photothermal therapy via stabilization of polyubiquitinated substrates in the proteasomal degradation pathway. ACS Nano 14, 10688–10703 (2020).
Li, B. et al. Aggregation-induced emission-based macrophage-like nanoparticles for targeted photothermal therapy and virus transmission blockage in monkeypox. Adv. Mater. 36, 2305378 (2024).
Xi, D. et al. NIR light-driving barrier-free group rotation in nanoparticles with an 88.3% photothermal conversion efficiency for photothermal therapy. Adv. Mater. 32, 1907855 (2020).
Zhu, D. et al. Tumor-derived exosomes co-delivering aggregation-induced emission luminogens and proton pump inhibitors for tumor glutamine starvation therapy and enhanced type-I photodynamic therapy. Biomaterials 283, 121462 (2022).
Wang, J., Gong, Q., Jiao, L. & Hao, E. Research advances in BODIPY-assembled supramolecular photosensitizers for photodynamic therapy. Coord. Chem. Rev. 496, 215367 (2023).
Liu, S. et al. Cationization-enhanced type I and type II ros generation for photodynamic treatment of drug-resistant bacteria. ACS Nano 16, 9130–9141 (2022).
Lu, J. et al. Spin manipulation engineering of photodynamic intermediates: magnetic amplification of oxyradicals generation for enhanced antitumor phototherapeutic efficacy. J. Am. Chem. Soc. 147, 18100–18109 (2025).
Cai, X. et al. Nanoparticles selectively regulate the generation and scavenging of multiple reactive oxygen species at designated locations and states. J. Am. Chem. Soc. 147, 21385–21399 (2025).
Yan, K. et al. Versatile nanoplatforms with enhanced photodynamic therapy: designs and applications. Theranostics 10, 7287–7318 (2020).
Lo, P.-C. et al. The unique features and promises of phthalocyanines as advanced photosensitisers for photodynamic therapy of cancer. Chem. Soc. Rev. 49, 1041–1056 (2020).
Xu, G. et al. A supramolecular photosensitizer derived from an Arene-Ru(II) complex self-assembly for NIR activated photodynamic and photothermal therapy. Nat. Commun. 13, 3064 (2022).
Zhang, D. Y. et al. Tumor microenvironment-responsive theranostic nanoplatform for guided molecular dynamic/photodynamic synergistic therapy. ACS Appl. Mater. Interfaces 13, 17392–17403 (2021).
Jian, H. J. et al. Super-cationic carbon quantum dots synthesized from spermidine as an eye drop formulation for topical treatment of bacterial keratitis. ACS Nano 11, 6703–6716 (2017).
Liu, K. K. et al. Efficient red/near-infrared-emissive carbon nanodots with multiphoton excited upconversion fluorescence. Adv. Sci. 6, 1900766 (2019).
Rosenkrans, Z. T. et al. Selenium-doped carbon quantum dots act as broad-spectrum antioxidants for acute kidney injury management. Adv. Sci. 7, 2000420 (2020).
Cai, Y. et al. Insights on forming N,O-coordinated Cu single-atom catalysts for electrochemical reduction CO2 to methane. Nat. Commun. 12, 586 (2021).
Yang, H. et al. Hydrophobic carbon dots with blue dispersed emission and red aggregation-induced emission. Nat. Commun. 10, 1789 (2019).
Gong, N. et al. Carbon-dot-supported atomically dispersed gold as a mitochondrial oxidative stress amplifier for cancer treatment. Nat. Nanotechnol. 14, 379–387 (2019).
Geng, B. et al. Near-infrared phosphorescent carbon dots for sonodynamic precision tumor therapy. Nat. Commun. 13, 5735 (2022).
Jia, Q. et al. A magnetofluorescent carbon dot assembly as an acidic H2O2 -driven oxygenerator to regulate tumor hypoxia for simultaneous bimodal imaging and enhanced photodynamic therapy. Adv. Mater. 30, 1706090 (2018).
Song, R. W. et al. Triplet electron exchange in carbon nanodots-assisted long-persistent near-infrared chemiluminescence for oncology synergistic imaging and therapy. Adv. Sci. 12, 2411898 (2025).
Zhang, Y. et al. Carbon dots nanophotosensitizers with tunable reactive oxygen species generation for mitochondrion-targeted type I/II photodynamic therapy. Biomaterials 293, 121953 (2023).
Yan, Y. et al. Systematic bandgap engineering of graphene quantum dots and applications for photocatalytic water splitting and CO2 reduction. ACS Nano 12, 3523–3532 (2018).
Li, Y. et al. Enhancing the magnetic relaxivity of MRI contrast agents via the localized superacid microenvironment of graphene quantum dots. Biomaterials 250, 120056 (2020).
Luo, T. et al. Bifunctional cascading nanozymes based on carbon dots promotes photodynamic therapy by regulating hypoxia and glycolysis. ACS Nano 17, 16715–16730 (2023).
Xu, L. et al. Ultralong organic phosphorescent nanocrystals with long-lived triplet excited states for afterglow imaging and photodynamic therapy. ACS Appl. Mater. Interfaces 12, 18385–18394 (2020).
Dai, J. et al. Efficient near-infrared photosensitizer with aggregation-induced emission for imaging-guided photodynamic therapy in multiple xenograft tumor models. ACS Nano 14, 854–866 (2020).
Xu, J. et al. All-in-one theranostic nanomedicine with ultrabright second near-infrared emission for tumor-modulated bioimaging and chemodynamic/photodynamic therapy. ACS Nano 14, 9613–9625 (2020).
Liu, M. et al. Golgi apparatus-targeted aggregation-induced emission luminogens for effective cancer photodynamic therapy. Nat. Commun. 13, 2179 (2022).
Li, S. et al. Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids. Nat. Biomed. Eng. 4, 704–716 (2020).
Xin, Q., Ma, H., Wang, H. & Zhang, X. D. Tracking tumor heterogeneity and progression with near-infrared II fluorophores. Exploration 3, 20220011 (2023).
Jiang, K. et al. Red, green, and blue luminescence by carbon dots: full-color emission tuning and multicolor cellular imaging. Angew. Chem. Int. Ed. 54, 5360–5363 (2015).
Zhang, L. et al. Cancer-macrophage hybrid membrane-camouflaged photochlor for enhanced sonodynamic therapy against triple-negative breast cancer. Nano Res 15, 4224–4232 (2022).
Yang, G. et al. Acceptor engineering for optimized ROS generation facilitates reprogramming macrophages to M1 phenotype in photodynamic immunotherapy. Angew. Chem. Int. Ed. 60, 5386–5393 (2021).
Xiao, T. et al. Macrophage membrane-camouflaged responsive polymer nanogels enable magnetic resonance imaging-guided chemotherapy/chemodynamic therapy of orthotopic glioma. ACS Nano 15, 20377–20390 (2021).
Yu, N. et al. Near-infrared photoactivatable semiconducting polymer nanocomplexes with bispecific metabolism interventions for enhanced cancer immunotherapy. Nano Today 46, 101600 (2022).
Li, Y. et al. Sono/photodynamic nanomedicine-elicited cancer immunotherapy. Adv. Funct. Mater. 31, 2008061 (2020).
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 12375345 to L.S., 22278262 to D.P.), the Science and Technology Commission of Shanghai Municipality (No. 25ZR1402150 to B.G.), the Young Elite Scientists Sponsorship Program by CAST (No. 2023QNRC001 to B.G.), the Innovative Research Team of High-level Local Universities in Shanghai, and the cultivation project (ynms202103 to L.S.) from Shanghai Jiao Tong University affiliated Sixth People’s Hospital.
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B.G. and D.P. designed and directed the study, analyzed the data and wrote the manuscript. S.S. and L.S. directed the study and improved the manuscript. Z.Z., L.Y., and W.L. performed experiments and analyzed data. J.H. provided important suggestions and improved the manuscript. Y.W. and H.D. provided advice and technical help with cell experiments and mouse cancer models. All authors discussed the results and reviewed the manuscript.
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Zhang, Z., Yan, L., Li, W. et al. D-π-A sensitized carbon dots as long-lived type-I/Ⅱ photosensitizers for NIR-excited hypoxia-regulated photodynamic therapy. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71476-y
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DOI: https://doi.org/10.1038/s41467-026-71476-y
