LAUSR

ABSTRACT The past decade has witnessed a growing number of nanoparticulate drug delivery systems for cancer treatment. However, insufficient cellular uptake by cancer cells and the undesirable endo/lysosomal entrapment of internalized therapeutic drugs remain the “Achilles heel” of many developed nanoagents. Here, we develop a novel lipid raft‐responsive and light‐controllable polymeric drug for efficient cytosolic delivery of photosensitizers. Conjugating a photosensitizer protoporphyrin IX (PpIX) to a polyethylene glycol‐cholesterol polymer affords the amphiphilic drug (denoted as Chol−PEG−PpIX) that forms micelles in aqueous solutions. The Chol−PEG−PpIX with two hydrophobic units (cholesterol and PpIX) showed robust binding to plasma membranes and enabled significant cellular uptake via two pathways: (1) cholesterol moiety triggered the lipid raft‐mediated endocytosis of Chol−PEG−PpIX with minimized endo/lysosomal trafficking after internalization; (2) the membrane‐bound PpIX acted as a light‐controlled trigger and can augment the permeability of plasma membranes upon laser irradiation, allowing the rapid influx of extracellular Chol−PEG−PpIX within 5 min. For systemic drug delivery, Chol−PEG−PpIX was anchored on the surface of liposomes via in situ membrane modification, which substantially avoided nonspecific binding of Chol−PEG−PpIX to red blood cells during circulation. Besides, the Chol−PEG−PpIX‐anchored liposomes exhibited enhanced in vivo fluorescence, reduced liver uptake, prolonged tumor retention, and effective tumor ablation by photodynamic therapy. This work illustrates a new strategy for direct and efficient cytosolic delivery of photosensitizers, which may hold great promise in cancer therapy. Graphic abstract Figure. No caption available.