Ultrasound‐Guided Targeted Combination Therapy Integrating VEGFR Degradation Independent of a Specific Receptor, Mitochondrial Damage, and Sonodynamic Immunomodulation

Inhibiting the vascular endothelial growth factor-vascular endothelial growth factor receptor (VEGF-VEGFR) signaling pathway is clinically established for solid tumors, but durable efficacy is frequently limited by acquired resistance. Accumulating evidence links this resistance to metabolic plasticity, wherein tumors suppress glycolysis and gradually become dependent on mitochondrial respiration for survival, rendering mitochondrial inhibition a rational strategy to mitigate resistance. Recently, targeted protein degradation (TPD) has emerged as an event-driven modality for pathogenic protein elimination, but the degradation of membrane targets is still challenging due to limited transmembrane E3 ligases and heterogeneous lysosome-targeting receptor (LTR) expression. To overcome these challenges, we designed a multifunctional peptide-sonosensitizer conjugate (PSC) by covalently linking a VEGFR-targeting peptide, a mitochondria-homing peptide, and the clinically approved sonosensitizer verteporfin (VPN) via a gelatinase-cleavable linker. PSC self-assembles into stable nanoparticles with tumor-preferential accumulation and, upon ultrasound activation, generates reactive oxygen species (ROS) to induce oxidative degradation of VEGFR, thereby suppressing VEGFR signaling and angiogenesis. Following cellular internalization, enzymatic linker cleavage releases a mitochondria-targeted fragment that triggers mitochondrial depolarization and structural disruption, amplifying ROS-driven apoptosis. Moreover, sonodynamic immune modulation further potentiates antitumor efficacy. This study establishes a spatiotemporally controllablestrategy that is independent of a specific receptor and couples anti-angiogenic pathway blockade with mitochondrial vulnerability to address resistance and enable precision, immune-synergistic therapy.