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

ABSTRACT 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.