Strategies for Controllable siRNA Delivery in Gene Silencing and Cancer Therapy
Small interfering RNA (siRNA) holds promise for selective silencing of oncogenic drivers, yet its clinical translation is hindered by endosomal entrapment and inefficient cytosolic delivery. This review systematically examines the biological barriers to siRNA function, emphasizing that successful gene silencing requires not only cellular uptake but also endosomal escape, carrier dissociation, and RISC loading. We categorize current delivery strategies into carrier-free systems and stimuli-responsive carriers. Carrier-free approaches utilize coordination chemistry, molecular self-assembly, or peptide conjugation to form stable siRNA complexes that undergo intracellular dissociation. Stimuli-responsive carriers exploit endogenous tumor cues (e.g., acidic pH, elevated glutathione, specific enzymes, ATP) or exogenous triggers (e.g., light, ultrasound, magnetic fields) to achieve spatiotemporally controlled release. The review highlights recent advances in both strategies, with a focus on their application in cancer therapy. We critically assess the challenges that remain, including heterogeneity of tumor microenvironments, scalability of synthesis, and in vivo stability. Finally, we outline future directions for translating siRNA-based therapies into clinical practice, emphasizing the need for rational design of delivery systems that integrate multiple stimuli-responsiveness and active targeting to overcome biological barriers.