Separable Microneedles Composed of Hyaluronic Acid Derivatives and Acid-Labile Linkages for Transdermal Delivery of Biomimetic Nanoparticles and Synergistic Breast Cancer Therapy

Abstract This study was designed to develop a convenient, separable microneedle (MN) system capable of achieving a synergistic antitumor effect through combined chemotherapy and photothermal therapy. The MN comprises a water-soluble substrate and a cross-linked tip fabricated via methacrylated hyaluronic acid (HAMA) and a monomer containing orthoester bonds. The tip is loaded with dasatinib/sunitinib-based nanoparticles coated with 4T1 cell membranes (TCM@NPs), along with the photosensitizer IR820. The MN system demonstrates effective skin penetration and rapid separation of the base from the tip upon insertion, thereby significantly reducing the required application time and enhancing the drug delivery efficiency. The residual microneedle tip at the tumor site undergoes enzyme- and pH-triggered degradation, enabling the sustained and controlled release of therapeutic agents. In vivo studies in 4T1 tumor-bearing mice demonstrated that this microneedle system significantly suppressed tumor progression, reducing mean tumor volume to 84 mm3 (92.2% inhibition rate vs control). Therefore, this multifunctional platform represents a rational strategy for localized and synergistic combination therapy of breast cancer.