In Situ Needle-Free Injection of Multiretention Micelles for Melanoma Therapy with Multiomics Insights into Tumor Targeting and Immune Modulation

Melanoma is aggressive with limited treatment options. Paclitaxel (PTX) is effective but limited by poor solubility, systemic toxicity, and insufficient intratumoral retention. Here, we report an in situ needle-free platform that amplifies local PTX exposure via multiretention nanoscale mixed polymeric micelles composed of Soluplus and a dipotassium glycyrrhizinate-PEG-folic acid conjugate (DG-pp-FA). Needle-free intratumoral jet injection at the tumor site reduces needle-related barriers and discomfort. The micelles integrate thermoenabled local deposition and physical retention, pH-responsive stabilization and release in acidic tumor microenvironments, and folate-receptor targeting for enhanced uptake and selectivity. Central composite design optimization yielded stable micelles with a hydrodynamic size of 68 ± 3.8 nm, PDI of 0.08 ± 0.01, and 98 ± 0.11% PTX encapsulation efficiency, showing sustained release. Compared with free PTX, NF#PTX@Soluplus/DG-pp-FA improved tumor retention, increased cellular uptake, and more strongly inhibited melanoma proliferation, migration, and invasion. Single-cell sequencing, spatial transcriptomics, and proteomics revealed dual actions of direct tumor suppression and immune microenvironment remodeling, including increased leukocyte infiltration, extracellular matrix (ECM) reprogramming to improve penetration, enhanced immune activation, and reduced fibrosis. <i>In vivo</i> studies confirmed improved tumor localization, prolonged retention, lower toxicity, and good biocompatibility.