Tumor-retained lipid nanoparticle-microneedle systems for codelivery of SARS-CoV-2 mRNA and indocyanine green for synergistic immuno-photothermal therapy of superficial tumors.

The development of tumor-retained and minimally invasive mRNA and photothermal therapies for superficial malignant tumors, such as breast cancer, remains a significant challenge. In this study, we present a novel tumor-retained lipid nanoparticle-microneedle (LNP-MN) patch for localized co-delivery of mRNA and the photothermal agent indocyanine green (ICG). By optimizing LNP formulations, ICG loading methodology, mRNA-to-ICG ratio, and MN matrix composition, we achieved a balanced platform ensuring high mRNA transfection efficiency and robust ICG photothermal performance. This LNP-MN platform enabled efficient intratumoral deposition, demonstrating a 15.6-fold increase in tumor accumulation compared to intravenous administration. For the first time, SARS-CoV-2 spike mRNA was combined with ICG-mediated photothermal therapy (PTT) within a single system for superficial tumor treatment. In a 4 T1 breast cancer model, this combinatorial strategy achieved significant tumor growth inhibition (75.1 %), enhanced CD8+ T-cell infiltration, and minimized systemic toxicity, outperforming monotherapies. This study pioneers the integration of PTT and mRNA-based tumor-labeling immunotherapy in a minimally invasive MN platform, offering a promising strategy for enhanced superficial cancer therapy.