Engineering Protein Stability in Dissolving Microneedle Patches: Mechanistic Principles, Polymer Engineering, Formulation Strategies, and Clinical Translation for Insulin and Other Biologics

Protein therapeutics such as insulin, monoclonal antibodies, peptide hormones, cytokines, enzymes and vaccine antigens have revolutionized the treatment of chronic and complex diseases, but are currently constrained by adherence issues with frequent injection, cold-chain requirements and their intrinsic vulnerability to structural degradation. Dissolving microneedle (DMN) patches have recently been identified as a transdermal platform which allows minimally invasive, self-administered drug delivery and solid-state stabilization of fragile biologics. However, it is a significant challenge to keep the structural integrity and biological activity of proteins when developing the formulation, fabricating the microneedles, drying, storing the fabricates, and applying them to the skin. The mechanisms of molecular degradation (e.g., unfolding, aggregation, fibrillation, oxidation, deamidation, interface-induced denaturation) and stabilization (e.g., water replacement, vitrification, preferential hydration, and molecular confinement) all contribute to the stability of proteins in DMN matrices. Other processes also modulate these processes, such as polymer–protein interactions, residual moisture, glass-transition behavior, molecular mobility and microenvironmental physicochemical conditions. The rational engineering of polymer matrices, excipients systems and processing conditions therefore is the key to preserving a higher-order protein structure while providing sufficient mechanical properties, quick dissolution, higher drug loading efficiency and reproducible intradermal delivery. In recent years, a wide range of multifunctional biomaterials, hybrid polymer architectures, carrier-free insulin formulations and stimuli-responsive matrices have significantly broadened the design space for insulin and other biologic formulations that enables their stabilization during ambient and accelerated storage. Moreover, recent developments in biophysical characterization, solid-state analytical methods and computational modeling have helped to gain insight into formulation–structure–function relationships, and accelerated the rational optimization of protein-loaded DMN systems. Yet, there are still many difficulties to overcome for long-term stability, scalable manufacturing, quality-by-design implementation, regulatory standardization and global deployment. By combining mechanistic protein biophysics, pharmaceutical formulation and translational manufacturing, a platform for robust, cold-chain independent dissolving microneedles with a wide range of clinical applications across next-generation biologic therapeutics can be built.