Electrostatically Stabilized Light-Activated Membrane Delivery System: Overcoming Membrane Flexibility and Self-Repair to Enhance Tumor Therapy.

Cell membrane-coated nanoparticle-based delivery systems often struggle with inevitable drug leakage during the delivery process and inefficient drug release at the tumor site, resulting in unsatisfactory antitumor outcomes. Here, we present an electrostatically stabilized light-activated membrane delivery system (Hybrid membrane nanoparticles, [Hm]@NPs) for leak-free drug delivery, coupled with precisely site-specific and controllable drug release, to elevate cancer treatment. [Hm]@NPs are constructed by encapsulating an aggregation-induced emission (AIE) photosensitizer (Phenalen-1-one-quinoline malonitrile-thiophene tribenamine, Phe-Qui-T) into a positively charged reactive oxygen species (ROS)-responsive polymer (F127-TP-U11) to form a positively charged nanoparticle and then coating it with a negatively charged hybrid membrane containing red blood cell membrane and Panc-1 cell membrane. [Hm]@NPs with high stability effectively prevent drug leakage through electrostatic interaction between the hybrid membrane and nanoparticle. Simultaneously, the photosensitizer Phe-Qui-T with light-controlled ROS generation efficiently destroys both the ROS-responsive polymer and the hybrid membrane, ensuring precise and sufficient drug release while enabling photodynamic therapy (PDT), thereby augmenting antitumor efficacy. [Hm]@NPs show impressive tumor inhibition in pancreatic cancer mouse models, highlighting the potential of this light-controlled membrane-disruption strategy for advanced cell membrane-coated nanodelivery system design.