òòò½Íø

Science

Microneedle skin patches have emerged as a promising platform for transdermal vaccine delivery; however, their application to protein vaccines has been a challenging task because of the inadequate tip-loading and unsatisfactory stability. To tackle these challenges, we have developed a protein-capturing microgel-integrated microneedle skin patch (microgel patch) capable of stabilising protein cargoes and localizing them to the microneedle tips. Our study shows that the microgel patch enables efficient transdermal delivery of a recombinant SARS-CoV-2 protein vaccine in mice with a good safety profile, highlighting its potential as an effective transdermal vaccination platform.

Societal Impact

Compared with traditional hypodermic syringe needles, microneedle skin patches offer distinct advantages, such as minimal invasiveness, high patient compliance and reduced risk of infection. Despite such desirable features, the development of microneedle patches for transdermal protein delivery has been limited by the lack of effective means to enhance the tip-loading and stability of labile protein cargoes. Herein we propose an effective approach to improve the tip-loading capacity, storage stability and transdermal delivery performance of protein-loaded microneedle skin patches. The feasibility of our approach was demonstrated by using multiple recombinant proteins, including botulinum neurotoxin, human interferon alpha-2a and SARS-CoV-2 spike receptor-binding domain. The microneedle patch technology is expected to improve the quality of life of patients, particularly those with needle phobia, compromised immunity or fatal bleeding disorder and those requiring frequent injections to manage chronic conditions.

Technical Summary

Various microneedle skin patches have been explored till now for transdermal protein delivery, but only small dosages can be transdermally delivered due to the limited volume of microneedle tips. In addition, since proteins are prone to denaturation when exposed to variations in temperature, pH, osmolality and other factors, preserving their activity during manufacturing, storage and transportation remains as a major roadblock to clinical translation of microneedle patches. In this study, we have designed polymeric microgels bearing phenolic dimers, which can serve as a protein-capturing agent via the formation of multiple protein-phenolic interactions, such as hydrophobic, hydrogen-bonding and π–π stacking interactions.

Introduction of these microgels in the patch manufacturing process enables localisation of protein cargoes to the microneedle tips, thus resulting in a significant enhancement in their transdermal delivery performance. Our microgel patches achieve 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 conventional patches lacking the microgels. In a mouse model, transdermal delivery of CpG oligonucleotide-adjuvanted RBD using microgel patches induces a more rapid neutralising antibody response than the conventional patches and subcutaneous injection. Overall, these results support the potential utility of microgel patches for transdermal delivery of recombinant proteins for diverse prophylactic and therapeutic applications.

Figure 1. Schematic illustration of a protein-capturing microgel-integrated skin patch (microgel patch) capable of not only localizing protein cargoes in the tip portion but also stabilizing them via multiple protein-phenolic interactions.

References

Bae KH*, Liang K*, Seow BYL, Loh JM, Li L, Lai F, Chen Q, Kurisawa M, Thng STG, Yang YY. Protein-Capturing Microgel-Integrated Microneedle Array Patches for Enhanced Tip-Loading, Storage Stability, and Transdermal Delivery of Recombinant Proteins. Small (2026) e12624. doi: 10.1002/smll.202512624