PLEKHA5-targeted photothermal-gene combination therapy via mPDA@DMEA@siRNA nanoparticles suppresses melanoma progression.

Melanoma is an aggressive skin malignancy characterized by high metastatic potential and resistance to current systemic therapies, highlighting the need for novel molecularly targeted and minimally invasive treatment strategies. Photothermal therapy enables localized tumor ablation with reduced systemic toxicity; however, its monotherapeutic efficacy is limited by incomplete tumor elimination and adaptive cellular stress responses. To address these limitations, we employed an integrative bioinformatics approach combining bulk transcriptomic analysis, weighted gene co-expression network analysis, single-cell RNA sequencing, survival analysis, and three machine learning algorithms to identify melanoma-relevant therapeutic targets. This analysis identified PLEKHA5 as a key melanoma-associated gene with significant prognostic value and preferential expression in malignant cell populations. We then engineered a mesoporous polydopamine-based nanoplatform, mPDA@DMEA@siRNA, for concurrent PLEKHA5 gene silencing and near-infrared (NIR)-driven photothermal therapy. In this system, mPDA serves as the photothermal core, and surface modification with N,N-dimethylethylenediamine (DMEA) enables efficient electrostatic siRNA loading. The nanoplatform exhibited favorable physicochemical properties, broad NIR absorption, and potent photothermal conversion. In vitro, mPDA@DMEA@siRNA combined with NIR irradiation induced A375 melanoma cell death, enhanced reactive oxygen species generation, and silenced PLEKHA5 at both mRNA and protein levels. In an A375 xenograft model, mPDA@DMEA@siRNA markedly suppressed tumor growth, with histological analyses showing decreased proliferation, increased apoptotic cell death, reduced angiogenesis, and effective PLEKHA5 silencing. Systemic biosafety was supported by normal hematological parameters, stable serum biochemical indices, and absence of major organ pathology. Collectively, this study identifies PLEKHA5 as a candidate therapeutic target and demonstrates that mPDA@DMEA@siRNA is a promising nanoplatform for photothermal-gene combination therapy in melanoma.