Plasma membrane-anchorable photosensitizing nanomicelles for lipid raft-responsive and light-controllable intracellular drug delivery.

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.