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

TL;DR

This paper introduces a new proteoliposome system that uses heat to both trigger cancer cell damage and block protective heat shock proteins, improving the effectiveness of photothermal therapy.

Contribution

A novel photothermal-responsive proteoliposome system that sequesters heat shock proteins via phase transition to overcome cancer thermoresistance.

Findings

VOx@ELP-PL induces hyperthermia and enhances HSP expression in cancer cells.

ELP-PL undergoes liquid–liquid phase separation to sequester HSPs and disrupt thermoresistance.

The system promotes immunogenic cell death and shows effective cancer treatment in a mouse model.

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 (VOx NZs) incorporated in the lumen, referred to as VOx@ELP-PL. Upon photoirradiation, the enclosed VOx 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, VOx@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 VOx@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.

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