A Carrier-Free Ultrasound-Responsive Polyphenol Nanonetworks with Enhanced Sonodynamic-Immunotherapy for Synergistic Therapy of Breast Cancer

Sonodynamic therapy (SDT) is an efficient non-invasive strategy for treating breast cancer. However, the therapeutic efficacy of SDT is greatly limited by various defense mechanisms in the tumor microenvironment, particularly the overexpression of B-cell lymphoma-2 (Bcl-2). In this study, based on drug self-delivery systems, a carrier-free ultrasound-responsive polyphenol nanonetwork (GTC) was developed to enhance SDT by inhibiting Bcl-2. A one-pot method, involving the interaction of the polyphenolic Bcl-2 inhibitor gossypol (GOS), transferrin, and the sonosensitizer chlorin e6 (Ce6), was used to synthesize the GTC. The GTC was efficiently internalized by MDA-MB-231 and 4T1 cells through specific binding to transferrin receptors, and no external carriers were needed. After cellular internalization, GOS increased the lethality of Ce6-mediated SDT by reducing the expression of the Bcl-2 protein, which caused multiple toxic effects. RNA-seq analysis confirmed the transcriptomic alterations in oxidative stress and apoptotic pathways induced by the GTC nanosystem. In vivo studies revealed that GOS-assisted SDT not only eliminated tumors through sonodynamic effects and triggered immunogenic cell death but also enhanced sono-immunotherapy, thus effectively suppressing distant tumors and metastasis. This study might provide insights into carrier-free nanomedicines for SDT-based synergistic tumor therapy.