Stimuli-Responsive Nanocarriers for Efficient siRNA Delivery in Cancer Therapy

Abstract Small interfering RNA (siRNA) is emerging as one of the most promising therapeutic agents for the treatment of various diseases. Safe and efficient carriers are essential for delivering siRNA to cells in that naked siRNA is susceptible to nuclease degradation and difficult to penetrate the cell membrane owing to its large molecular size and highly negative charge. Although some nanocarriers, including lipid nanoparticles, polymeric nanoparticles, carbon dots, inorganic nanomaterials, and extracellular vesicles, have been developed to deliver siRNA, low endosomal escape efficiency and insufficiently controlled intracellular release remain major problems. Stimuli-responsive nanocarriers could respond to pathological or intracellular signals and undergo changes in size, surface charge, carrier stability, or siRNA release behavior, enabling controlled siRNA release and improved endosomal escape while maintaining stability during circulation. In this review, representative advances in stimuli-responsive nanocarriers for siRNA delivery are summarized, focusing on pH-, redox-, reactive oxygen species-, enzyme-, light-, temperature-, magnetic-field-, and ultrasound-responsive delivery nanocarriers. Through the integration of insights from material design, responsive mechanisms, siRNA release behavior, endosomal escape ability, and therapeutic applications, this review provides valuable guidance for the rational design of advanced stimuli-responsive siRNA nanocarriers to strengthen endosomal escape efficiency and enhance overall therapeutic efficacy.