Polypeptide nanoparticles obstruct glucose supply for NIR-II fluorescence-guided tumor starvation and enhanced mild photothermal therapy

Photothermal therapy (PTT) utilizes localized hyperthermia above 50 °C generated by nanomaterials upon exposure to near-infrared (NIR) laser light for effective cancer cell eradication. Yet, in high-temperature PTT, tumor cells develop heat stress tolerance due to elevated heat shock protein (HSP) levels, diminishing therapeutic efficacy. Moreover, excessive heat can trigger inflammatory conditions and promote cancer metastasis. Targeting the glycolytic pathway in highly metabolically active tumor cells offers a promising strategy for inducing starvation therapy, capitalizing on their vigorous energy demands amidst rapid proliferation. Here, we synthesized a highly luminous NIR-II dye, FNF, followed by its encapsulation alongside myricetin (My) within amphiphilic polypeptide carriers through a self-assembly method. The resulting nanoparticles exhibited great NIR-II imaging capabilities and boasted a notable photothermal conversion efficiency of 55.58 %. Furthermore, My effectively impeded glucose transport facilitated by glucose transporter protein 1 (GLUT1), curtailing glucose supply to tumor cells. This interference disrupted mitochondrial energy production, resulting in decreased adenosine triphosphate (ATP) synthesis and subsequent downregulation of HSP70 expression. By leveraging this approach, which targeted HSP expression via GLUT1 inhibition, we enhance the efficacy of PTT while achieving a synergistic effect for mild photothermal therapy through starvation. STATEMENT OF SIGNIFICANCE: High expression of heat shock proteins (HSPs) in cancer cells impairs the efficacy of photothermal therapy (PTT) and triggers inflammation or metastasis, among other effects. Rapid malignant proliferation of tumor cells results in high energy metabolism, so interfering with their glucose metabolism to inhibit the glycolytic process is a feasible route for tumor starvation therapy. Here, we employed an amphiphilic polypeptide encapsulated photosensitizer (FNF) and myricetin (My) to construct nanoparticles with both NIR-II imaging capability and high photothermal conversion efficiency (55.58 %). Among them, My blocked glucose transport mediated by glucose transporter protein 1 (GLUT1), reduced the glucose supply and ATP synthesis in cancer cells, and then down regulated HSP70 expression. Thus, this strategy achieves starvation synergistic mild photothermal therapy through metabolic disruption.