Overcoming lysosomal barrier via V-ATPase: an exosome-based co-delivery platform for combined chemo/RNAi therapy against breast cancer

Overcoming the lysosomal entrapment of nanotherapeutics remains a pivotal challenge for efficient drug delivery. Herein, we developed a nano-delivery system, designated as CEL-TPP@siSurvivin/TDNP NPs, consisting of a self-assembled nanocore formed by triphenylphosphine (TPP)-modified celastrol (CEL) and siSurvivin, encapsulated within turmeric-derived nanoparticles (TDNPs), for effective tumor treatment through a combined chemotherapy and gene therapy approach. The TPP modification confers mitochondrial targeting capability to CEL, which acts combinedly with siSurvivin-mediated gene silencing to significantly enhance tumor cell apoptosis. Notably, once the NPs enter cells and become sequestered within lysosomes, they induce the upregulation of the V-ATPase subunits ATP₆V₁A/ATP₆V₁G₁. It hyperactivates lysosomal proton pumps, driving excessive acidification of the lysosomal lumen, which in turn facilitates NPs escape and ultimately enhances the silencing efficiency of the delivered siSurvivin. Furthermore, in vivo studies validated that the nano-delivery system exhibits potent antitumor efficacy in a 4T1 murine breast cancer model while maintaining a favorable biosafety profile. This study presents a novel strategy to overcome the lysosomal escape challenge in nanomedicine, while also establishing an efficient and low-toxicity delivery platform for combined chemotherapy and gene therapy with promising clinical translation prospects.