Photothermal-Responsive Phase Transition of Proteoliposomes for Heat Shock Protein Sequestering against Cancer Thermoresistance

Photothermal therapy (PTT) has garnered considerable attention for its noninvasive and localized treatment advantages. However, in response to PTT-induced hyperthermia, cancer cells increase the expression level of heat shock proteins (HSPs) and activate thermoresistance to shield themselves from heat-induced damage, thereby diminishing the efficacy of PTT. To overcome thermoresistance, here we have developed an on-demand responsive proteoliposome (PL) system. This system consists of PLs formed by a phospholipid conjugate of an elastin-like polypeptide (ELP) with vanadium oxide nanozymes (VO x NZs) incorporated in the lumen, referred to as VO x @ELP-PL. Upon photoirradiation, the enclosed VO x NZs generate a photothermal effect, inducing hyperthermia and enhancing HSP expression in cancer cells. Concurrently, as the temperature surpasses a critical threshold, ELP-PL undergoes liquid–liquid phase separation (LLPS) in situ, transitioning from a liposome state to ELP coacervate droplets. In the hyperthermic cancer cells, ELP coacervate droplets sequester and insulate the up-regulated HSPs, disrupting the thermoprotective response of thermoresistant cancer cells. Moreover, VO x @ELP-PL combines peroxidase-catalyzed generation of toxic hydroxyl radicals with coacervate droplet-mediated sequestration of HSPs, leading to potentiated immunogenic cell death both in vitro and in vivo. In a mouse model of colon cancer, intravenously injected VO x @ELP-PL showed marked tumor enrichment and resulted in highly effective cancer treatment. Altogether, this system presents a novel strategy to counteract thermoresistance by sequestering HSPs via LLPS of ELP-PL, thereby augmenting the effectiveness of PTT in cancer therapy.