• • Endosomal escape efficiency is a critical bottleneck: even with high cellular uptake, siRNA must escape endosomes before lysosomal degradation to achieve functional gene silencing; inefficiencies at this step result in high uptake but weak silencing.
• • Carrier-free systems leverage coordination chemistry, molecular self-assembly, or peptide conjugation to achieve stable siRNA delivery and intracellular dissociation, offering a simplified formulation without additional excipients.
• • Stimuli-responsive carriers utilize endogenous cues (pH, GSH, enzymes, ATP) or exogenous triggers (light, ultrasound, magnetic fields) to enable spatiotemporally controlled release, enhancing RISC loading and gene silencing efficacy.
• • The tumor microenvironment is heterogeneous, presenting variable levels of pH, GSH, and enzymes; therefore, delivery systems must be designed to respond to a combination of cues to ensure robust release across different tumor regions.