Combined Enzyme-Responsive Nano-Peptide Drug with Photothermal Function for Effective Anti-Hepatocellular Carcinoma in Mice Model.

Introduction: The efficacy of photothermal therapy (PTT) for hepatocellular carcinoma (HCC) is severely constrained by tumor heat resistance, which is driven by heat shock protein (HSP) upregulation, alongside the limited tissue penetration of near-infrared (NIR) laser. Methods: An enzyme-responsive "peptide-drug" sequence (PD) was combined with gold nanorods (GNR) to construct a tumor-targeting microgel system (GNR/PD-M). The formulation was comprehensively evaluated in HepG2 cells and BALB/c nude mice bearing subcutaneous HCC xenografts, with key assessments including MMP-2-responsive drug release, in vitro cytotoxicity, mitochondrial and tumor targeting specificity, in vivo anti-tumor efficacy, and biosafety profiles. Results: In both cellular and animal models, the GNR/PD-M + laser irradiation group exhibited the strongest tumor cell inhibition. Mechanistically, this treatment significantly downregulated HSP90 expression and disrupted mitochondrial function, thereby overcoming tumor heat resistance and reducing tumor cell viability. Consistently, the in vivo anti-tumor effect of GNR/PD-M + laser was markedly superior to that of the control groups. Conclusion: The GNR/PD-M system synergistically enhances PTT efficacy against HCC by mitochondrial targeting and heat resistance reversal, representing a promising strategy for intelligent and targeted drug delivery.