Melanin@PLGA/Nuciferine Nanoparticles for Enhanced Photothermal Therapy of Hepatocellular Carcinoma by Promoting Autophagy.

Background: The advent of nanotechnology has enabled photothermal therapy (PTT) to emerge as a novel, noninvasive modality for thermal ablation of hepatocellular carcinoma (HCC). However, the thermal stress induced by PTT can trigger autophagy in tumor cells, contributing to treatment resistance. Consequently, a promising strategy to enhance PTT efficacy involves concurrently disrupting tumor cell autophagy, given that autophagy overactivation can ultimately induce cell death. Methods: MPN was designed for precise magnetic resonance imaging (MRI) diagnosis of HCC and guidance of PTT for HCC. PTT-mediated heating accelerated nuciferine release from the MPN. The released nuciferine then promoted autophagosome formation and autophagic degradation, thereby enhancing PTT efficacy via autophagy overactivation. Results: MPN successfully encapsulated melanin and loaded nuciferine, exhibiting favorable encapsulation efficiency and drug-loading capacity. Upon 808 nm near-infrared (NIR) irradiation, MPN exhibited excellent photothermal conversion efficiency and robust stability. In vitro experiments confirmed that nuciferine effectively promoted autophagosome maturation in HCC cells, with enhanced autophagy induction observed when it was combined with PTT. Furthermore, MPN exhibited high MRI contrast. In vivo studies validated its selective accumulation in HCC tumors, enabling safe and effective thermal ablation and subsequent suppression of post ablation HCC growth via autophagy overexpression. Conclusion: MPN enhanced the T1-weighted MRI signal for accurate tumor localization and demonstrated superior photothermal properties. Moreover, MPN potentiated PTT by inducing autophagy overactivation in HCC cells, thereby enhancing ablation efficacy and inhibiting post-PTT tumor growth.