Stimuli-Responsive Nanocarriers for Transdermal siRNA Delivery: Mechanisms, Challenges, and Therapeutic Strategies

Background: Small interfering RNA (siRNA) holds therapeutic promise for dermatological diseases, but clinical translation is limited by the stratum corneum barrier and the instability of naked siRNA. Nanocarrier-based systems offer effective solutions by enhancing skin penetration, improving siRNA stability, and enabling targeted intracellular delivery. Methods: This review synthesizes current evidence on nanocarrier-mediated transdermal siRNA delivery. Key design parameters: particle size, surface charge, degradability, and morphology are evaluated for their roles in skin permeation and intracellular trafficking. Stimuli-responsive nanocarriers (pH, enzymatic, light, temperature) and physical enhancement strategies, including microneedles, sonophoresis, and laser ablation, are also reviewed. Results: Lipid-polymer hybrid nanoparticles demonstrate notable advantages in stability, biocompatibility, and co-delivery capability. Stimuli-responsive systems enable spatiotemporal control of siRNA release, while physical enhancement technologies significantly improve cutaneous permeability. Disease-specific delivery strategies tailored to pathological microenvironments including psoriasis, melanoma, and chronic wounds illustrate the feasibility of adapting material composition, structural parameters, and responsiveness to different therapeutic contexts. Conclusion: Advances in intelligent nanomaterials, responsive carrier engineering, and physical facilitation approaches provide a solid foundation for clinically viable transdermal siRNA therapies. Future development will benefit from integrating precise release control with disease-tailored delivery strategies to overcome biological barriers and optimize therapeutic outcomes.