Protein‐Capturing Microgel‐Integrated Microneedle Array Patches for Enhanced Tip‐Loading, Storage Stability, and Transdermal Delivery of Recombinant Proteins

Microneedles have gained increasing attention as an ideal device for transdermal drug delivery; however, their application to proteins has been a challenging task because of their inadequate tip-loading and unsatisfactory stability. Herein, we report the development of a microgel-integrated microneedle array patch (MI-MAP) capable of not only localizing protein cargoes in the tip portion but also stabilizing them via protein-phenolic interactions. Incorporation of protein-capturing microgels allows enrichment of protein cargoes within the tip region of microneedles, resulting in a significant enhancement in their transdermal delivery performance. MI-MAP enables more effective stabilization of labile recombinant proteins, such as botulinum neurotoxin, human interferon alpha-2a, and SARS-CoV-2 spike receptor-binding domain (RBD), during storage at 25 °C for 28 days compared to the counterpart lacking the microgels (HA-MAP). Transdermal delivery of CpG-adjuvanted RBD using MI-MAP elicits a more rapid neutralizing antibody response and germinal center B-cell proliferation in mice than HA-MAP and subcutaneous injection, without causing any severe inflammation. This study presents a potential strategy for improving tip-loading and storage stability of recombinant proteins within microneedle structures.