Dissolving Microneedles with Plant‐Derived Vesicles for Synergistic Chemo‐Photothermal Delivery in Cutaneous Squamous Cell Carcinoma Therapy

ABSTRACT Cutaneous squamous cell carcinoma (CSCC) presents significant treatment challenges due to chemotherapy‐associated toxicity, drug resistance, and poor tumor permeability. Here, we developed a synergistic chemo‐photothermal therapy (PTT) platform using octa‐arginine (O‐Arg) modified Pueraria lobata ‐derived vesicles (Arg‐PDVs) co‐loaded with palbociclib (Pab) and indocyanine green (ICG), integrated into dissolving microneedles (MNs) for localized CSCC treatment. Arg‐PDVs were prepared via differential centrifugation, functionalized with a cell‐penetrating peptide O‐Arg, and characterized for physicochemical properties, demonstrating enhanced tissue penetration. Pab and ICG were efficiently encapsulated into Arg‐PDVs (APPI) and loaded into optimized MNs with sufficient mechanical strength for transdermal delivery. In vitro studies revealed superior cellular uptake, photothermal conversion efficiency, and cytotoxicity against CSCC cells. In vivo evaluation in a CSCC tumor model showed that APPI‐MNs achieved synergistic tumor inhibition (92.96% ± 3.84%), significantly surpassing chemotherapy‐alone (54.17% ± 4.57%) or PTT‐alone (75.18% ± 3.87%) groups ( p < 0.001). The MN system facilitated localized drug release, minimized systemic toxicity, and exhibited excellent biocompatibility without skin damage. This study highlights a plant vesicle‐based MN platform for chemo‐PTT synergy, offering a promising strategy for enhancing CSCC treatment efficacy while reducing off‐target effects.