Hypoxia-reinforced antitumor RNA interference mediated by micelleplexes with programmed disintegration

The performance of polycation-mediated siRNA delivery is often hurdled by the multiple systemic and cellular barriers that pose conflicting requirements for materials properties. Herein, micelleplexes (MPs) capable of programmed disintegration were developed to mediate efficient delivery of siRNA against XIAP (siXIAP) in a hypoxia-reinforced manner. MPs were assembled from azobenzene-crosslinked oligoethylenimine (AO), acid-transformable diblock copolymer PPDHP with conjugated photosensitizer, and siXIAP. AO efficiently condensed siXIAP via electrostatic interaction, and PPDHP rendered additional hydrophobic interaction with AO to stabilize the MPs against salt. The hydrophilic PEG corona enhanced the serum stability of MPs to prolong blood circulation and promote tumor accumulation. After internalization into cancer cells, the endolysosomal acidity triggered shedding of PPDHP, exposing AO to induce endolysosomal escape. Then, light irradiation generated lethal amount of ROS, and concurrently aggravated intracellular hypoxia level to degrade AO into low-molecular weight segments, release siXIAP, and potentiate the XIAP silencing efficiency. Thus, siXIAP-mediated pro-apoptosis cooperated with generated ROS to provoke pronounced anti-cancer efficacy against Skov-3 tumors in vitro and in vivo. This study provides a hypoxia-instructed strategy to overcome the multiple barriers against anti-cancer siRNA delivery in a programmed manner. The success of RNA interference (RNAi) heavily depends on delivery systems that can enable spatiotemporal control over siRNA delivery. Herein, we developed micelleplexes (MPs) constructed from hypoxia-degradable, azobenzene-crosslinked oligoethylenimine (AO) and acid-responsive, photosensitizer-conjugated diblock copolymer PPDHP, to mediate efficient anti-tumor siRNA (siXIAP) delivery via programmed disintegration. MPs possessed high salt/serum stability and underwent acid-triggered PPDHP detachment to promote endolysosomal escape. Then, light irradiation aggravated hypoxia to trigger AO degradation and intracellular siXIAP release, which cooperated with photodynamic therapy to eradicate tumor cells. This study presents a new example of hypoxia-degradable polycation to mediate hypoxia-reinforced RNAi, and it also renders an effective strategy to overcome the complicated extracellular/intracellular barriers against systemic siRNA delivery.