Programmatically Controllable Activation of Sonodynamic Therapeutics with Bioorthogonal-Based Mitochondria-Specific Exogenous Agents toward Accurate Tumor Elimination

Sonodynamic therapy (SDT) mediated by endogenous stimuli-activated sonosensitizing prodrugs is faced with problems such as low specificity, tumor heterogeneity, and uncontrollability. Utilizing bioorthogonal reactions as exogenous stimuli to programmatically activate the prodrugs has been identified as a potential solution to these problems. Herein, we present a mitochondria-specific sonosensitizing system for programmatically controllable activation of sonodynamic therapeutics based on the Staudinger reaction by rationally designing a mitochondrial-targeting bioorthogonal trigger (TP) and a mitochondria-targeting sonosensitizing nanoprodrug (MA-NPs). The MA-NPs is enriched inside the mitochondria of the tumor cell driven by the mitochondrial membrane potential. The enrichment of MA-NPs and the subsequently loaded TP within mitochondria initiate Staudinger reactions, which promote the disintegration of MA-NPs to release sonosenitizing methylene blue (MB). Then, under ultrasound irradiation, MB produces reactive oxygen species (ROS) to damage the mitochondria of tumor cells and induce apoptosis, which effectively inhibits tumor development and facilitates the effects of SDT. This research presents an innovative strategy for the advancement of exogenous activation agents capable of selectively and efficiently activating prosonosensitizers and achieving controllable and effective SDT.