Natural Biodegradable Polymer-Based Microneedles for Controlled Drug Delivery: A Rational Design Framework and Translational Perspectives

Microneedle (MN) technology has emerged as a promising minimally invasive platform for transdermal drug delivery, enabling efficient transport of therapeutic agents across the stratum corneum while improving patient compliance. In recent years, natural biodegradable polymers have gained increasing attention in microneedle fabrication due to their biocompatibility, biodegradability, and functional versatility. This review provides a comprehensive overview of recent advances in natural polymer-based microneedle systems, including material selection, fabrication strategies, and mechanisms of controlled drug release. Importantly, beyond conventional descriptive analysis, this work introduces a rational design framework that systematically integrates therapeutic objectives, polymer properties, mechanical performance, and release kinetics to guide the development of optimized microneedle platforms. The review further addresses key translational challenges, including mechanical limitations, manufacturing scalability, stability concerns, and regulatory considerations. In addition, emerging trends such as stimuli-responsive systems, nanocarrier integration, and personalized drug delivery approaches are discussed. Notably, data-driven strategies, including artificial intelligence (AI) and machine learning, are highlighted as promising tools for predicting system performance, optimizing formulation parameters, and accelerating the development of next-generation microneedle-based drug delivery systems. Overall, this work shifts the paradigm from empirical formulation toward a predictive, engineering-driven design strategy, offering valuable insights to advance the clinical translation of smart microneedle technologies.