Plasma membrane activatable polymeric nanotheranostics with self-enhanced light-triggered photosensitizer cellular influx for photodynamic cancer therapy
To address the issue of low cellular uptake of photosensitizers by cancer cells in photodynamic therapy (PDT), we designed a smart plasma membrane-activatable polymeric nanodrug by conjugating the photosensitizer protoporphyrin IX (PpIX) and polyethylene glycol (PEG) with glycol chitosan (GC). The as-prepared GC-PEG-PpIX can self-assemble into core-shell nanoparticles (NPs) in aqueous solution and the fluorescence of PpIX moieties in the inner core is highly quenched due to strong π–π stacking. Interestingly, when encountering plasma membranes, the GC-PEG-PpIX NPs can disassemble and stably attach to plasma membranes due to the membrane affinity of PpIX moieties, which effectively suppresses the self-quenching of PpIX, leading to significantly enhanced fluorescence and singlet oxygen (1O2) production upon laser irradiation. The massively produced 1O2 can compromise the integrity of the plasma membrane, enabling the influx of extracellular nanoagents into cells to promote cell death upon further laser irradiation. Through local injection, the membrane anchored GC-PEG-PpIX enables strong physical association with tumor cells and exhibits highly enhanced in vivo fluorescence at the tumor site. Besides, excellent tumor accumulation and prolonged tumor retention of GC-PEG-PpIX were realized after intravenous injection, which ensured its effective imaging-guided PDT.