A natural synergy-based nanosystem co-delivering siRNA and paclitaxel for full-stage apoptosis promotion in melanoma.

Paclitaxel (PTX) kills tumor cells by stabilizing microtubules to induce apoptosis, but its efficacy is limited by resistance mediated by the anti-apoptotic protein survivin. Targeted inhibition of survivin with siRNA could synergistically enhance PTX-induced apoptosis; however, nucleic acid-based therapeutics, such as siRNA, exhibit high instability and susceptibility to degradation, making their efficacy highly dependent on specialized delivery systems. Thus, co-delivery systems for PTX and siRNA are critical to achieving synergistic antitumor activity. Natural products present several advantages, including wide availability, high biocompatibility, and multi-target synergistic effects, offering promising approaches for constructing a co-delivery system. In this study, a co-delivery system integrating siRNA and PTX based on natural products was developed. Ginsenoside Rg3 (Rg3) not only serves as the structural backbone but also enhances tumor-targeting capability and inhibits tumor cell migration. The edible cationic polymer chitooligosaccharide (COS) efficiently encapsulates siRNA, ensuring safe and efficient delivery. This co-delivery system based on natural synergy enables multi-level cooperation: Rg3 mediates targeted transport, PTX triggers apoptosis, and COS-assisted siRNA silences survivin, thereby ensuring precise targeting and promoting complete tumor apoptosis, highlighting a promising strategy for the application of natural products in cancer therapy.