Hierarchical Cascade-Activated Microneedle Patches for Photothermal and Chemotherapy.

Chemotherapy and photothermal therapy (PTT) are recognized as effective strategies in cancer treatment. However, the challenge remains in effectively targeting these therapeutic modalities to the tumor site to improve therapeutic effects. Here, a novel hierarchical cascade-activated microneedle (MN) patch (MN_DOX@M_ICG) for photothermal and bioorthogonal chemotherapy was developed. The MN patch was fabricated by integrating hydrogel microspheres (M_ICG) containing tetrazine-functionalized indocyanine green (Tz-ICG) into the MN arrays. Upon irradiation with near-infrared light, Tz-ICG with high photothermal conversion efficiency can elevate the temperature of MN, facilitate PTT, and trigger the release of trans-cyclooctene-conjugated doxorubicin (TCO-DOX) encapsulated in MN. Then, the gradually released Tz-ICG from M_ICG can react with TCO-DOX via a specific inverse electron-demand Diels-Alder bioorthogonal reaction, thereby restoring the anticancer activity of DOX. Consequently, MN_DOX@M_ICG can efficiently eradicate tumor cells in vitro and significantly inhibit the growth of postsurgical melanoma by combining PTT with bioorthogonal chemotherapy. These findings highlight the practical value of such a hierarchical cascade-activated MN patch for versatile drug delivery and biomedical applications.