The loss of phosphatase and tensin homolog (PTEN) can lead to resistance to immune checkpoint inhibitors (ICIs) in melanoma, thereby promoting immune evasion and tumor progression. These effects can be reversed by restoring PTEN expression, reactivating antitumor immunity, and enhancing therapeutic responses. Here, we develop a hyaluronate-conjugated lipid nanoparticle (HA-LNP) with HA-dimyristoyl glycerol (DMG) for the noninvasive, transdermal delivery of PTEN mRNA. This amphiphilic lipid enables stable HA integration during LNP self-assembly, effectively replacing PEG, supporting particle stability, biocompatibility, and CD44-mediated targeting. The resulting HA-LNP efficiently encapsulate large mRNA payloads, penetrate the skin, and selectively target CD44-expressing tumor cells. In vitro, PTEN mRNA@HA-LNP restores PTEN expression, induces immunogenic cell death (ICD), and reduces melanoma cell viability. In vivo, topical application results in deep skin and tumor penetration, significantly inhibiting tumor growth and enhancing immune activation with minimal toxicity. Taken together, these results highlight HA-LNP as a promising, clinically translatable platform for localized, mRNA-based cancer immunotherapy.
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