Stimulus-Detonated Biomimetic “Nanobomb” with Controlled Release of HSP90 Inhibitor to Disrupt Mitochondrial Function for Synergistic Gas and Photothermal Therapy

Photothermal therapy (PTT) is considered a promising treatment for tumors, however, its therapeutic efficacy is limited by the overexpression of heat shock proteins (HSPs). Herein, a stimuli-responsive theranostic nanoplatform (denoted as M/D@P/E-P) was designed for synergistic gas therapy and enhanced PTT. This nanoplatform was fabricated by the load of manganese carbonyl (MnCO, CO donor) in dendritic mesoporous silicon (DMS), followed by the coating with polydopamine (PDA), and loading of epigallocatechin gallate (EGCG, HSP90 inhibitor). Upon near-infrared (NIR) irradiation, the photothermal effect of PDA not only induces apoptosis of tumor cells but also triggers the controlled drug release of MnCO and EGCG. Moreover, the acidity and H2O2-rich tumor microenvironment can render the degradation of released MnCO, followed by triggering the release of CO gas. CO-initiated gas therapy can realize to disrupt the mitochondrial function, which can accelerate cell apoptosis and down-regulate HSP90 expression by decreasing intracellular ATP. The combination of EGCG and MnCO effectively can reduce the thermo-resistance of tumor and improve the PTT sensitivity. In addition, the released Mn2+ enables T1-weighted magnetic imaging of tumors. The approach was systematically evaluated and verified both in vitro and in vivo. Taken together, this study afforded a prime paradigm of applying this strategy for enhanced cancer photothermal therapy via mitochondrial dysfunction.