α-Mangostin-Loaded Gold Nanorod-Integrated MOF Nanoplatform for Photoacoustic Imaging-Guided Photothermal Therapy of Melanoma Involving Pyroptosis-Related Signaling

Purpose: Melanoma remains a highly aggressive malignancy with limited therapeutic options, largely due to poor tumor selectivity and acquired resistance to conventional treatments in advanced disease. This study aimed to develop a gold nanorod (AuNR)-integrated metal-organic framework (MOF) theranostic nanoplatform for photoacoustic imaging-guided photothermal therapy of melanoma and to investigate its association with pyroptosis-related signaling. Methods: The α-MG/AuNR@ZIF-8/FA-PEG nanoplatform was rationally engineered to co-deliver α-mangostin (α-MG) and AuNRs within a pH-responsive ZIF-8 matrix, with folate-PEG surface modification to enhance cellular uptake. Physicochemical properties were characterized by TEM, DLS, and FTIR. Drug release profiles, photothermal conversion efficiency, hemocompatibility, and short-term in vivo tolerability were systematically evaluated. In vitro cytotoxicity and cellular uptake were assessed in A375 melanoma cells, and in vivo antitumor efficacy was validated in tumor-bearing mice. The pyroptosis-related signaling pathway was investigated by Western blotting. Results: The nanoplatform exhibited favorable colloidal stability, pH-responsive controlled drug release, and excellent photothermal performance, with a hydrodynamic diameter of approximately 212.1 nm, a zeta potential of approximately − 22 mV, an α-MG loading capacity of 21.89 ± 0.02%, and a peak temperature of approximately 56.5 °C under 808 nm laser irradiation (1.0 W/cm 2 ). FA-PEG modification was associated with enhanced cellular uptake, while time-dependent tumor accumulation of the nanoplatform was observed in vivo. The combined treatment produced greater antitumor effects than the tested comparator groups, with an approximately 70% tumor growth inhibition rate. Mechanistically, treatment was associated with increased oxidative stress, activation of the canonical NLRP3/caspase-1/GSDMD pyroptosis-related pathway, and enhanced cell death. AuNR-mediated photothermal heating further strengthened these responses, suggesting that the improved antitumor efficacy may involve the combined effects of α-MG-induced oxidative stress, photothermal injury, and activation of pyroptosis-related signaling. Conclusion: This multifunctional nanoplatform integrates α-MG delivery, real-time photoacoustic imaging, and controlled photothermal activation, and its antitumor effects were associated with activation of pyroptosis-related signaling. These findings support further investigation of this platform for image-guided melanoma therapy.