Cryomicroneedle Arrays for Biotherapeutics Delivery.

Biotherapy offers a promising approach for treating a variety of diseases. However, the lack of advanced delivery systems remains a significant barrier to improve the efficacy, safety, and cost-effectiveness of biotherapeutics. The microneedle, as a minimally invasive drug delivery tool, has demonstrated considerable potential in biotherapeutic applications. Despite this promise, challenges remain in fabricating microneedles that effectively preserve the bioactivity of biotherapeutics. Emerging as a novel solution, cryomicroneedles (cryoMNs) employ cryogenically molded ice matrices that exploit phase-transition thermodynamics. The metabolic stasis induced by cryoimmobilization preserves biomolecular conformation and cellular viability. Moreover, the ice-reinforced architectures achieve an optimal balance between mechanical penetration capacity and post-insertion dissolution kinetics, overcoming the rigidity-flexibility trade-off in traditional dissolving microneedles. Current research prioritizes three breakthrough directions: material innovation for cryocompatible polymer-ice interfaces, cold-chain optimization strategies to enhance payload viability, and innovations in medical application scenarios. Notably, preclinical successes in regenerative tissue engineering and thermostable vaccine platforms highlight cryoMNs' potential to bridge precision medicine and global health equity. This review provides an overview of recent advancements in cryoMNs and discusses the potential challenges and future directions for the development of cryoMNs-mediated biotherapeutics delivery.