An HSP90-inhibitory thermosensitive hydrogel enhances photothermal therapy against triple-negative breast cancer

Triple-negative breast Cancer (TNBC) is highly aggressive and prone to recurrence, and durable therapeutic efficacy is often difficult to achieve with monotherapy. Photothermal therapy (PTT) offers advantages such as minimal invasiveness and spatiotemporal controllability and induces tumor cell death through localized hyperthermia. However, thermal stimulation simultaneously activates protective heat-stress responses in tumor cells, among which the inducible upregulation of heat shock protein 90 (HSP90) enhances thermotolerance and consequently compromises the efficacy of PTT. To overcome this limitation, we proposed a synergistic strategy based on HSP90 inhibition to induce tumor cell Apoptosis while sensitizing tumors to PTT, and constructed an intratumorally injectable thermosensitive hydrogel for localized drug delivery. The HSP90 Inhibitor geldanamycin (GA) was loaded into mesoporous polydopamine (MPDA) to form MGA, which was subsequently encapsulated within a PNIPAM/β-glucan composite thermosensitive hydrogel, yielding MGA@Gel. Both in vitro and in vivo studies demonstrated that MGA@Gel markedly enhanced antitumor efficacy under near-infrared (NIR) laser irradiation and effectively suppressed HSP90-associated heat-stress tolerance. Notably, in a 4T1 tumor-bearing mouse model, a single intratumoral injection established a sustained local drug depot. When combined with NIR laser irradiation, this system enabled efficient tumor suppression, pronounced downregulation of HSP90 signaling, increased Apoptosis, and reduced tumor cell proliferation. These findings confirm that GA, by blocking the heat-stress protective pathway, effectively potentiates the antitumor effects of PTT. Overall, we developed a thermosensitive in situ hydrogel delivery system that enhances PTT via HSP90 inhibition, thereby overcoming tumor thermoresistance and providing a promising strategy for precise local treatment of TNBC.