<p>Photothermal therapy (PTT) has emerged as a promising strategy for treating solid tumors and topical infections by converting the incident light energy into localized heat using photothermal agents. Among these, gold nanoparticles (GNPs) are particularly attractive due to their strong surface plasmon resonance, tunable surface chemistry, biocompatibility and scalability. However, their limited biodegradability and inefficient clearance remain significant translational challenges. In this study, we have developed gold-coated calcium peroxide nanoparticles (CPAu-NPs) that offer dual advantages, enhanced photothermal conversion and intrinsic reactive oxygen species generation. The self-release of oxygen and hydrogen peroxide from CPAu-NPs addresses tumor hypoxia, a key barrier to effective therapy. To further augment therapeutic efficacy, we incorporated Sorafenib, a multi-kinase inhibitor known to induce ferroptosis and inhibit tumor progression in melanoma, a cancer type marked by dysregulated iron metabolism and vulnerability to ferroptosis. This combinatorial approach disrupts critical survival pathways while promoting lipid peroxidation, potentially overcoming resistance to standard treatments. Additionally, we explored the antifungal potential of this system, recognizing the increased susceptibility of immunocompromised cancer patients to fungal infections. Our results suggest that CPAu-NPs, in combination with Sorafenib, provide a multifunctional theranostic platform capable of targeting melanoma cells, modulating the tumor microenvironment, and addressing opportunistic fungal infections.</p>