Spatially Decoupled Piezoelectric Hydrogel with Trauma-Driven Migration of Engineered Platelets for Divergent Mitochondrial Fate Programming in Postoperative Cancer Therapy

Abstract Postoperative recurrence and metastasis remain major obstacles in solid tumor therapy because surgical intervention creates a spatially conflicting microenvironment. Here, a spatially decoupled piezoelectric hydrogel (BP@Gel) was developed to enable spatially divergent mitochondrial fate programming across the tumor-surgical-margin interface. Engineered platelets (BPs) were constructed by integrating barium titanate (BTO) piezoelectric nanoparticles with native platelets to couple piezocatalytic activity with trauma-responsive migration. BPs were subsequently embedded within a catechol-modified hydrogel designed to scavenge diffusible reactive oxygen species (ROS) and spatially segregate tumoricidal activity from tissue-protective signaling. Postoperative inflammatory cues and tumor-derived chemoattractants guided 72.7% of BP homing to residual tumor sites. Selective accumulation at tumor sites was mediated through P-selectin/CD44 recognition to enable spatially confined catalytic activation. Upon ultrasound stimulation, intracellular piezocatalysis was triggered within migrated BPs, producing ROS to induce mitochondrial dysfunction, immunogenic cell death, and robust antitumor immune activation. In parallel, ROS diffusion into the surgical margin was reduced via a hydrogel barrier. BP-derived H2 levels increased by 1.4-fold, thereby supporting mitophagy induction, mitochondrial homeostasis restoration, and anti-inflammatory macrophage polarization. In a triple-negative breast cancer resection model, BP@Gel achieved eradication of residual lesions, increased CD8+ T cell infiltration by 35.5-fold compared to the control, and established long-term immune memory, accompanied by an 83.5% reduction in lung metastatic burden. This work establishes spatially decoupled piezocatalytic therapy as a strategy for directing opposing mitochondrial fates across heterogeneous postoperative tissue compartments.