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

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.

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.

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.

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.