Biodegradable and Piezoelectric Mn-Doped Hydroxyapatite for Sonodynamic Immunotherapy.

Abstract

The tumor microenvironment usually exhibits immunosuppressive characteristics, and pyroptosis is an effective method to stimulate antitumor immune responses. However, the current metal-ion-overload strategy to induce pyroptosis is hindered by the ion buffering system within the cell, which inhibits the release of exogenous ions. Herein, a biodegradable manganese-doped hydroxyapatite (Mn-HAP) with ultrasound (US) triggered continuous reactive oxygen species (ROS) modulation is proposed. Mn-HAP is defined as a sonoimmune stimulator because it functions as both a sonosensitizer and an immune agent. Before degradation, Mn-HAP exhibits an enhanced sonodynamic antitumor effect through the Mn-doping oxygen vacancies. Moreover, the built-in electric field induced by US activates the cell membrane-related ion channels and induces Ca²⁺ influx. Following the degradation of Mn-HAP in the slightly acidic tumor microenvironment, the released Ca²⁺ and ROS produced in sonodynamic therapy promote pyroptosis, while Mn²⁺ activates the cGAS-STING pathway, triggering innate immunity and further enhancing the effect of pyroptosis-induced immunotherapy. This work provides a promising strategy for engineering biodegradable materials for the sonodynamic immunotherapy of solid tumors.