Charge-Reversal Drug Delivery Systems in Cancer Nanomedicine

Charge-reversal drug delivery systems represent a dynamic class of nanocarriers engineered to modulate surface charge in response to specific tumour-associated stimuli. Under physiological conditions such systems often bear a neutral or negative surface charge to minimise nonspecific interactions and prolong circulation time. Upon encountering the acidic, reductive or enzyme-rich milieu of the tumour microenvironment, these nanocarriers undergo controlled physicochemical transformations, converting to a positive charge that enhances cellular adhesion, membrane penetration and intracellular uptake. By harnessing polymers, inorganic scaffolds and bioresponsive linkers, charge-reversal designs facilitate improved tumour accumulation, deeper tissue penetration and precise payload release. Recent advances have focused on multifunctional platforms that combine pH-responsiveness with secondary triggers such as temperature or redox potential, enabling site-specific activation and minimising off-target toxicity. The versatility of charge-reversal approaches extends to a broad range of therapeutic agents, including chemotherapeutics, RNA and photosensitisers, opening new avenues for combination therapies and personalised treatment regimens. This intelligent control over surface properties addresses long-standing challenges in nanomedicine, notably the trade-off between systemic stability and efficient tumour uptake, and establishes a foundation for next-generation oncological interventions.

Research from Nature Portfolio

Recent studies have demonstrated dual-responsive mesoporous silica nanoparticles grafted with poly(dimethylaminoethyl methacrylate) shells. These hybrids remain inert at physiological pH and normal temperature, but upon exposure to the acidic and slightly elevated thermal conditions of tumours, the polymer undergoes protonation and solvation, triggering a rapid surface charge shift from neutral or negative to positive. This activation facilitates controlled release of model drugs such as doxorubicin and methotrexate in acidic environments, while maintaining stability under normal conditions, thereby reducing systemic toxicity and enhancing selective cytotoxicity in cancer cells. In parallel, hyperbranched polymeric nanocarriers incorporating pH-sensitive amine groups and redox-cleavable disulfide bonds have been engineered to shrink in size and reverse surface charge in response to tumour pH and high glutathione concentrations. These smart carriers exhibit accelerated tumour penetration, heightened cellular uptake and markedly improved apoptotic induction in breast cancer models, illustrating the synergistic benefit of combining charge reversal with size-tunable behaviour.

Charge-Reversal Drug Delivery Systems in Cancer Nanomedicine publication trend

The graph below shows the total number of articles in charge-reversal drug delivery systems in cancer nanomedicine across all publications each year (not limited to Nature Index journals).

Technical terms

Charge-reversal nanocarrier: A nanoparticle designed to change surface charge in response to a specific stimulus, typically from neutral/negative to positive, to enhance tumour targeting and uptake.

Tumour microenvironment: The local cellular and molecular milieu surrounding a tumour, characterised by features such as acidic pH, elevated reductive species and specific enzyme activities.

pH-responsive: A material property enabling structural or surface changes when exposed to a defined range of acidity, commonly exploited for site-specific drug release.

Redox-responsive: The capacity of a system to undergo chemical transformations, such as bond cleavage, in the presence of reducing agents like glutathione, prevalent in tumour cells.

Mesoporous silica nanoparticles: Inorganic carriers with uniform pore structures that enable high drug loading and tunable surface functionalisation for responsive release.

Hyperbranched polymeric nanocarrier: A three-dimensional polymer network with abundant terminal groups, facilitating multifunctional triggers and size-adaptive behaviour.

2,3-Dimethylmaleic anhydride (DMMA): An acid-labile linker commonly used to mask amino groups, which hydrolyses under mildly acidic conditions to reveal surface charges.

References

1. Advances in 2,3-Dimethylmaleic Anhydride (DMMA)-Modified Nanocarriers in Drug Delivery Systems. Pharmaceutics (2024).
2. Charge-Reversal Nano-Drug Delivery Systems in the Tumor Microenvironment: Mechanisms, Challenges, and Therapeutic Applications. International Journal of Molecular Sciences (2024).
3. Dual pH- and temperature-responsive poly(dimethylaminoethyl methacrylate)-coated mesoporous silica nanoparticles as a smart drug delivery system. Scientific Reports (2023).
4. Charge reversal nano-systems for tumor therapy. Journal of Nanobiotechnology (2022).
5. Activated Charge-Reversal Polymeric Nano-System: The Promising Strategy in Drug Delivery for Cancer Therapy. Polymers (2016).
6. Dual pH/redox-responsive hyperbranched polymeric nanocarriers with TME-trigger size shrinkage and charge reversible ability for amplified chemotherapy of breast cancer. Scientific Reports (2024).