Lin He, Yan Zhou, Mingjian Chen, Lanlin Qi, Min Zhang, Shunyuan Xie, Lamei Liu, Yuchen Wu, Kemin Wang, Jianbo Liu, Xiaoxiao He
Melanoma is a highly aggressive skin cancer with limited therapeutic efficacy under conventional monotherapy. Synergistic photothermal/photodynamic therapy (PTT/PDT) offers a promising therapeutic strategy, yet its sequential application remains challenging due to inadequate transdermal drug delivery, tumor hypoxia, and insufficient spatiotemporal control. Herein, we proposed a self-oxygenating microneedle (MN) patch for sequential PTT/PDT of melanoma by loading multifunctional black phosphorus (BP) nanocomposites into a hyaluronic acid (HA) matrix. Specifically, the multifunctional BP nanocomposites, denoted as CaO2/BP@PDA, were rationally engineered on photothermally and photodynamically active BP nanosheets via the integration of oxygen-generating calcium peroxide (CaO2) and a protective layer of polydopamine (PDA). Under sequential near-infrared (NIR) irradiation at 808 nm and 660 nm, the CaO2/BP@PDA provided sustained oxygen generation and exhibited synergistic PTT/PDT effects, achieving a high photothermal conversion efficiency (η = 42.26%) and a ∼2-fold enhancement in PDT efficacy compared with bare BP. Furthermore, the MN platform could enable efficient transdermal delivery and intratumoral accumulation. In vivo evaluation in a mouse melanoma model demonstrated that the CaO2/BP@PDA MN patches, combined with self-oxygenation and controllable light irradiation, could induce mild photothermia and enhanced reactive oxygen species (ROS) generation, achieving ∼97% melanoma inhibition without evident systemic toxicity. Mechanistically, the programmable PTT/PDT mediated by the CaO2/BP@PDA MN patches could amplify stress signaling, and drive metabolic disruption and apoptotic activation, ultimately leading to melanoma cell death. With these features, the proposed MN patches demonstrated effective sequential PTT/PDT against melanoma, highlighting their potential for clinical translation.