Tumor microenvironment responsive biocompatible piezoelectric nanoplatform for pH-responsive MRI guided chemo/piezodynamic therapy of subcutaneous glioma

Malignant cancers, which are highly aggressive and therapeutically resistant with limited treatment approaches, dual piezo-chemodynamic therapy to kill cancers both sharply under ultrasound (US) stimuli and persistently under acid conditions would be an ideal choice. To achieve tumor microenvironment (TME)-activated and size-minimized precision cancer theranostics for highly effective treatment outcomes remains a significant challenge. Herein, chitosan-functionalized Mn-doped bismuth ferrite (CMBFO) nanoparticles are developed for TME-responsive magnetic resonance imaging (MRI)-guided chemodynamic therapy (CDT) and piezodynamic therapy (PZDT) against subcutaneous tumors. The chitosan functionalization not only improves biocompatibility and cellular uptake but also facilitates pH-triggered Mn 2+ release through protonation of NH 2 groups, leading to loosening of the coating. This process endows T 2 -MRI contrast and activates the Fenton-like reaction to generate reactive oxygen species (ROS) for CDT. Concurrently, US stimulation induces the piezocatalysis, producing ROS for PZDT. This dual ROS-generating system demonstrates synergistic effects. In vitro and in vivo studies show that CMBFO accumulates specifically in the TME, with pH-triggered MRI signal peaking at 5.1 pH and 6 h post-injection, achieving over 95% tumor cell lethality under US with negligible systemic toxicity. This study establishes CMBFO as a multifunctional nanoplatform integrating tumor-specific MRI, pH-responsive drug release, and dual ROS-mediated therapy, offering a promising strategy for effective and safe tumor treatment.