Generic Optimized Synthesis of Biomimetic Hollow Mesoporous Nanosonosensitizers for Tumor-Homing Mutually-Reinforced Sono-Metalloimmunotherapy

Sonodynamic therapy (SDT) is widely regarded as a promising noninvasive antitumor strategy. However, conventional porphyrin-based sonosensitizers usually suffer from severe aggregation-caused quenching (ACQ), poor tumor accumulation, and limited immunogenic cell death (ICD) induction, which collectively restrict efficient intratumoral reactive oxygen species (ROS) generation and therapeutic efficacy. Herein, we develop a generic “ in situ framework co-hybridization” method to construct a series of small-sized hollow mesoporous nanosonosensitizers (PHs) with diverse organosilica hybridization of porphyrins to enhance the ultrasound (US)-activated ROS yield. The biocompatible PH with the utmost porphyrin incorporation is chosen to encapsulate digoxin (DIG) into its cavity (DPH). To prevent premature DIG leakage and enable acidity-responsive Ca 2+ release, the tailored DPH is further biomineralized with calcium phosphate (CaP) and subsequently camouflaged with a cancer cell membrane (CCM), endowing DPHCM with both high structural stability and tumor-homing capability. Harnessing the homologous targeting properties of CCM, DPHCM achieves enriched tumor accumulation, thus prompting intratumoral acidity-responsive CaP degradation for sequential release of Ca 2+ and DIG. Under external US irradiation, DPHCM elicits DIG/CaP dual-driven Ca 2+ overload-mediated metal ion interference therapy (MIT) and porphyrin-mediated SDT, both of which reinforce each other to trigger robust ICD, thereby promoting systemic antitumor immunity for effective tumor regression. This functionally optimized biomimetic nanosonosensitizer enables the synergistic integration of MIT and SDT, culminating in DIG-amplified sono-metalloimmunotherapy with mutually reinforced immune activation.