Self-modifying NanoEnhancers facilitating lysosomal escape for cGAS-STING cascading activation in tumor immunotherapy

Targeting mitochondria has emerged as an effective approach in recent tumor immunotherapy. While nanosized carriers have been utilized for therapeutic drug delivery, their retention in lysosomes diminishes their efficacy in targeting mitochondria. Despite the use of polycationic materials and peptides to facilitate lysosomal escape through the proton sponge effect and destabilization of lysosomal membranes, concerns persist regarding their stability and biocompatibility. Our objective is to exploit Oroxylin A (OA), a polyphenolic compound, to synthesize metal-polyphenolic complexes, capitalizing on OA's inherent lysosomal self-modifying properties to achieve efficient lysosomal escape. Herein, we report the fabrication of polyphenol-based OA@Mn@3-TYP nanoenhancers, assembled with hyaluronic acid (HA) and denoted as OMT NEs, designed for effective lysosomal escape and targeted drug delivery to mitochondria. These nanoenhancers exhibit a positive targeting ability towards tumor cells and facilitate lysosomal escape through spontaneous glucuronidation and sialic acid transporter mechanisms. The incorporation of OA and 3-TYP in the nanoenhancers leads to a cascading effect resulting in mitochondrial dysfunction and subsequent release of mitochondrial DNA (mtDNA). Upon activation of the Mn 2+ -enhanced cGAS-STING pathway by the released mtDNA, a synergistic anti-PD-1 immunotherapy effect is augmented, ultimately enhancing anti-tumor treatment.

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