Mitochondrial‐Targeted Ultrasmall Hydrophobic Cationic Graphene Nanosheets Potentiating Tumor Photoimmunotherapy

Abstract Mitochondria‐targeted drug delivery is a promising strategy to potentiate anti‐tumor efficacy. Current mitochondria‐targeting nano‐delivery strategies are mainly based on modification of lipophilic cation or targeting peptides. Due to endo/lysosomal capture and size limitation from mitochondrial outer membrane pores, neither approach guarantees efficient mitochondrial entry of the modified nanosystems. Herein, an ultrasmall hydrophobic cationic graphene oxide (GO‐ODA) based nanoplatform is developed for cascading of endo/lysosomal escape and precise inner mitochondrial membrane (IMM) targeting. The functional cascading originates from the strong Brownian motion and high edge density of the ultrasmall hydrophobic cationic GO‐ODA, which increases the frequency of edge‐induced scratching and lipid extraction against bio‐membranes during its random movement. Photosensitizers (PSs) with different charges are used as model therapeutics and loaded onto GO‐ODA surface, followed by co‐encapsulated within hyaluronic acid based amphiphile (IPHD) to form IPHD/GO‐ODA@PSs nanoparticles. The PSs loading dose‐optimized GO‐ODA@PSs are validated to feature membrane‐interactive properties for penetration, and prominently accumulate to IMM with inherent electronegativity. Upon laser irradiation, GO‐ODA@PSs induce severe mitochondrial dysfunction both in vitro and in vivo, and thus not only potentiate tumor inhibition, but also significantly enhance tumor immunogenicity through activating the cGAS‐STING pathway and GSDME‐mediated pyroptosis. It ultimately elicits a strong systemic antitumor immune response.