J-aggregated NIR-II IR-820-based theranostic γ-PGA-nanoplatform for NO-enhanced photothermal therapy of cervical cancer

Overcoming thermoresistance and achieving precise, efficient tumor therapy remain major challenges. Heat shock protein 70 (HSP70) expression and autophagy activation are two major cellular defense mechanisms associated with thermal resistance. However, strategies that target both mechanisms to improve tumor treatment efficacy remain limited. Herein, this study presents a novel type of near-infrared II (NIR-II)-responsive theranostic nanoplatform (IR-820@γ-PGA/Arg NPs, PIRA NPs) that integrates photothermal therapy (PTT), photodynamic therapy (PDT), nitric oxide (NO)-mediated gas therapy (GT), and dual-pathway inhibition mechanisms to overcome thermal resistance. The theranostic nanoplatform utilizes a γ-polyglutamic acid (γ-PGA) to encapsulate the NIR-II dye IR-820, which forms stable J-aggregates to improve NIR-II fluorescence emission and photothermal conversion efficiency. The nanoplatform adsorbs L-arginine (Arg) and releases NO under 808 nm laser excitation, exhibiting excellent photothermal properties and NIR-II fluorescence emission for precise tumor treatment. PIRA NPs overcome photothermal resistance via two pathways: suppressing HSP70-mediated thermoresistance and disrupting the autophagy-lysosomal degradation pathway (LC3B/p62 axis) through Arg-derived NO generation. This dual-pathway blockade effectively neutralizes tumor defenses, achieving a 92.7% tumor inhibition rate with minimal systemic toxicity. The γ-PGA framework enhances the stability of J-aggregates and their biocompatibility, further improving therapeutic efficacy. This work provides a versatile nanotherapeutic platform based on a promising strategy for reversing thermoresistance and achieving highly efficient cancer therapy.