Nanoigniter-Integrated Microneedle Patches for Boosted Photothermal-Mediated Multimodal Therapy: <i>In Situ</i> Tumor Microenvironment Igniting Strategy

Although photothermal therapy (PTT) has emerged as a promising strategy for tumor treatment, the antitumor efficiency is still unsatisfactory due to incomplete tumor ablation. Therefore, we propose a tailored <i>in situ</i> tumor microenvironment (TME) igniting strategy that leverages tumor extracellular metabolic heterogeneity (EMH) to transform metabolites into antitumor components. In this study, polydopamine (PDA) with photothermal performance was formulated into nanoparticles with polyethylenimine. Subsequently, lipoxygenase (LOX) and catalase (CAT) were adsorbed onto the nanoparticle surface, forming the PDA@CL nanoigniter, which was further integrated into microneedle patches. Upon penetration into tumors, the nanoigniters are rapidly released and accumulate in the deep tumor sites, and considerable free fatty acids (FFAs) are generated by PTT. Under abundant H₂O₂, CAT decomposes H₂O₂ to supply O₂, which efficiently helps LOX in catalyzing FFAs to promote lipid peroxide generation and induce tumor ferroptosis. Subsequently, the release of tumor-associated antigens promotes tumor-associated macrophages toward the M1 phenotype and stimulates dendritic cell maturation, thereby activating antitumor immune responses. Consequently, the proposed system established a PTT/ferroptosis/immunotherapy multimodal therapy to form a positive feedback loop of tumor-killing, demonstrating significant antitumor efficacy. Our research provides a versatile framework for leveraging EMH to enhance photothermal-mediated multimodal therapy.