Abstract
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.