Citation: Jawadi, Z.; Yang, C.; Haidar, Z.S.; Santa Maria, P.L.; Massa, S. Bio-Inspired Muco-Adhesive Polymers for Drug Delivery Applications. Polymers 2022, 14, 5459. https://doi.org/10.3390/ polym14245459 Academic Editor: Yury A. Skorik Received: 14 November 2022 Accepted: 4 December 2022 Published: 13 December 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). polymers Review Bio-Inspired Muco-Adhesive Polymers for Drug Delivery Applications Zina Jawadi 1,† , Christine Yang 1,† , Ziyad S. Haidar 2,3,4,5, * , Peter L. Santa Maria 1, * and Solange Massa 1 1 Department of Otolaryngology—Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA 2 BioMAT’X I+D+i (HAiDAR R&D&I LAB), Universidad de los Andes, Santiago 7620001, Chile 3 Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los Andes, Santiago 7620001, Chile 4 Programa de Doctorado en BioMedicina, Facultad de Medicina, Universidad de los Andes, Santiago 7620001, Chile 5 Department of Biomaterials and BioEngineering, Facultad de Odontología, Universidad de los Andes, Santiago 7620001, Chile * Correspondence: zhaidar@uandes.cl (Z.S.H.); petersantamaria@stanford.edu (P.L.S.M.) † These authors contributed equally to this work. Abstract: Muco-adhesive drug delivery systems continue to be one of the most studied for controlled pharmacokinetics and pharmacodynamics. Briefly, muco-adhesive polymers, can be described as bio- polymers that adhere to the mucosal (mucus) surface layer, for an extended residency period of time at the site of application, by the help of interfacial forces resulting in improved drug delivery. When compared to traditional drug delivery systems, muco-adhesive carriers have the potential to enhance therapeutic performance and efficacy, locally and systematically, in oral, rectal, vaginal, amongst other routes. Yet, the achieving successful muco-adhesion in a novel polymeric drug delivery solution is a complex process involving key physico-chemico-mechanical parameters such as adsorption, wettability, polymer chain length, inter-penetration and cross-linking, to list a few. Hence, and in light of accruing progress, evidence and interest, during the last decade, this review aims to provide the reader with an overview of the theories, principles, properties, and underlying mechanisms of muco-adhesive polymers for pharmaceutics; from basics to design to characterization to optimization to evaluation to market. A special focus is devoted to recent advances incorporating bio-inspired polymers for designing controlled muco-adhesive drug delivery systems. Keywords: mucoadhesive polymers; mucoadhesion; drug delivery; bioinspiration; BioPolymers 1. Introduction The pursuit of the ideal drug delivery strategy has led to the exploration of a variety of platforms to facilitate highly desirable, controlled, efficient and personalized drug de- livery [1–3]. Herein, biomimetics and bio-inspiration, or in other words, the way nature, with a minimum of resources, seems to design, assemble, and produce high-performance materials, is perhaps a valuable and interesting model and source of inspiration for the de- sign of novel polymer-based and hybrid drug delivery systems with advanced application safety and therapeutic properties and functionalities [3]. Such might also help overcoming the limitations and avoiding the un-wanted side-effects of traditional platforms. Bio-adhesion, or muco-adhesion, herein is defined as the adherence of materials, via attractive inter-facial forces, for an extended period of time with the mucosal (mucus) surface layer, typically from the oral route [1]. Originally pioneered by ophthalmologists to increase the bio-availability of drugs through controlled release drug delivery, muco- adhesive polymer technology has recently been used to enhance therapeutic residency and performance for systemic and local drug delivery systems through buccal, nasal, vaginal, and rectal routes [2–6]. Over the past decades, muco-adhesive polymer-based Polymers 2022, 14, 5459. https://doi.org/10.3390/polym14245459 https://www.mdpi.com/journal/polymers