Formulation, sterilization, and clinical evaluation of microneedles for vaccine and biologic delivery: A review.

Microneedles (MNs) are minimally invasive devices that facilitate transdermal delivery by creating micropores in the stratum corneum, the skin's outermost barrier. This property renders them particularly suitable for the delivery of biologics - large, structurally complex, and often unstable therapeutic agents such as proteins, peptides, nucleic acids, vaccines, and live cells or microorganisms. MNs offer a painless, self-administrable, and user-friendly alternative to conventional parenteral routes that often require trained personnel, generate hazardous waste, and result in low patient compliance. Since their first description in the 1990s, a wide variety of MN systems have been developed including solid, hollow, coated, dissolving, and hydrogel-forming, each with distinct fabrication and formulation requirements. This review provides a detailed and comparative discussion on formulation strategies tailored for the efficient delivery of different classes of biologics using MNs, with emphasis on the physicochemical and biological interactions at the skin interface. Special attention is given to sterilization, an often-overlooked yet regulatory-critical aspect, highlighting its importance for product safety, bioburden control, and biologic stability. Both terminal sterilization methods and aseptic manufacturing approaches are reviewed along with emerging alternatives such as self-sterilizing MNs. The review also provides a comprehensive overview of biologic-loaded MNs currently undergoing clinical evaluation. While previous reviews have focused on materials or fabrication aspects, this article presents a formulation-centric analysis, integrating physicochemical considerations, delivery challenges, and clinical translation pathways. The goal is to provide formulation scientists and translational researchers with a practical guide to MN-enabled biologic delivery systems, from bench to bedside.