A Sonosensitizing Nanoshuttle for Synergistic Hypoxia Relief and Immune Activation To Strengthen Sonodynamic Immunotherapy Against Triple-Negative Breast Cancer.

Abstract

The therapeutic efficacy of ultrasound-based tumor therapy is greatly hampered by tumor hypoxia and an immunosuppressive microenvironment. To address this, a sonosensitizing nanoshuttle (DPPM@HA) was constructed by coencapsulating oxygen-carrying perfluocarbon (PFC) and the STING agonist DMXAA into PCN222-Mn metal-organic frameworks, followed by hyaluronic acid (HA) modification for tumor-targeted delivery. After systemic administration, DPPM@HA accumulated at tumor sites and was specifically internalized by tumor cells. Ultrasound (US) irradiation facilitated the liberation of oxygen from DPPM@HA to alleviate hypoxia and immune suppression, while adequate oxygen supply and the US-sensitization effects of Mn-TCPP in DPPM@HA jointly promoted the burst of cytotoxic reactive oxygen species (ROS), exacerbating US-induced tumor damage and eliciting severe immunogenic tumor cell death. Meanwhile, high-valence manganese in the frameworks consumed by glutathione and was reduced to Mn(II), facilitating the destruction of DPPM@HA to release the loaded DMXAA. The resultant Mn²⁺ synergized with DMXAA to provoke STING activation, intensifying downstream immune responses. Besides the suppression of the unilateral tumor by DPPM@HA-mediated sonodynamic immunotherapy, the synergy with immune checkpoint blockade further enhanced systemic antitumor immunity, achieving potent effects against distant tumors and metastases. Summarily, the proposed DPPM@HA-mediated sonodynamic immunotherapy offered a promising strategy for high-performance sonodynamic immunotherapy.