Regulating Photosensitizer Metabolism with DNAzyme-Loaded Nanoparticles for Amplified Mitochondria-Targeting Photodynamic Immunotherapy

Mitochondria-specific photosensitizer accumulation ishighly recommendedfor photodynamic therapy and mitochondrial DNA (mtDNA) oxidative damage-basedinnate immunotherapy but remains challenging. 5-Aminolevulinic acid(ALA), precursor of photosensitizer protoporphyrin IX (PpIX), caninduce the exclusive biosynthesis of PpIX in mitochondria. Nevertheless,its photodynamic effect is limited by the intracellular biotransformationof ALA in tumors. Here, we report a photosensitizer metabolism-regulatingstrategy using ALA/DNAzyme-co-loaded nanoparticles (ALA & Dz@ZIF-PEG)for mitochondria-targeting photodynamic immunotherapy. The zeoliticimidazolate framework (ZIF-8) nanoparticles can be disassembled andrelease large amounts of zinc ions (Zn2+) within tumorcells. Notably, Zn2+ can relieve tumor hypoxia for promotingthe conversion of ALA to PpIX. Moreover, Zn2+ acts as acofactor of rationally designed DNAzyme for silencing excessive ferrochelatase(FECH; which catalyzes PpIX into photoinactive Heme), cooperativelypromoting the exclusive accumulation of PpIX in mitochondria via the"open source and reduced expenditure" manner. Subsequently,the photodynamic effects derived from PpIX lead to the damage andrelease of mtDNA and activate the innate immune response. In addition,the released Zn2+ further enhances the mtDNA/cGAS-STINGpathway mediated innate immunity. The ALA & Dz@ZIF-PEG system induced3 times more PpIX accumulation than ALA-loaded liposome, significantlyenhancing tumor regression in xenograft tumor models.