Citation: Gerardos, A.M.; Balafouti, A.; Pispas, S. Mixed Copolymer Micelles for Nanomedicine. Nanomanufacturing 2023, 3, 233–247. https://doi.org/10.3390/ nanomanufacturing3020015 Academic Editor: Boxin Zhao Received: 31 March 2023 Revised: 29 April 2023 Accepted: 15 May 2023 Published: 26 May 2023 Copyright: © 2023 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/). Review Mixed Copolymer Micelles for Nanomedicine Angelica M. Gerardos, Anastasia Balafouti and Stergios Pispas * Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece; amgerar@windowslive.com (A.M.G.); anastasia.mplft@gmail.com (A.B.) * Correspondence: pispas@eie.gr; Tel.: +30-2107273824 Abstract: Mixed micelles from copolymers in aqueous media have emerged as a valuable tool for producing functional polymer nanostructures with applications in nanomedicine, including drug delivery and bioimaging. In this review, we discuss the basics of mixed copolymer micelles’ design, structure, and physicochemical properties. We also focus on their utilization in biomedical applications using examples from recent literature. Keywords: mixed micelles; amphiphilic copolymers; RNA; DNA; drug delivery; nanomedicine 1. Introduction Nanotechnology is a field of study in which structures that consist of at least one dimension on the nanoscale (1–100 nm) are implemented in various applications [1–3]. The previous Horizon initiative (Horizon 2020) allocated around 2 billion euros in financing for projects in the booming field of nanotechnology [4]. Nanomedicine is a branch of medicine that employs a wide range of nanotechnology tools and aspects for therapy and diagnosis applications. Amongst a variety of nanomedicine formulations, biopolymer and synthetic polymer nanostructures are commonly explored owing to their potential as drug carriers [5]. Micelles, a subgroup of these nanostructures, are generated above a particular concentration (referred to as the critical micelle concentration (CMC)) and take on a sphere-like shape in most cases [6]. These structures are made up of a hydrophobic core that is ideal for retaining non-soluble substances and a hydrophilic corona that serves as a protective barrier from the aqueous environment [7,8]. In addition to enabling the solubilization of various valuable hydrophobic drugs, polymeric micelles offer a plethora of properties in terms of bio-applications induced by the functionalization of the normally hydrophilic outer shell, such as targeted drug delivery [9], or triggered drug release [10]. Polymeric micelles generated from a single type of copolymer may be deficient in several aspects. Given that these micelles have a finite total of building blocks, they are restricted in chemical and compositional variety and nanoscopic structure. An established but underutilized technique to address these issues is pairing different polymers to produce mixed micelles. There is the possibility to further improve the existing optimal features and eliminate some of the anticipated limitations of standard polymeric micelles with a minimum of effort in terms of synthetic techniques. Mixed micelles have often been shown to have considerable advantages, such as enhancing micelle stability and drug encapsulation effectiveness [11–14]. In the past, several studies on mixed micellar systems that achieved clinical stage research status have been presented in an excellent review by Cagel et al. [14]. Recently, an overview of different reports by Manjappa et al. highlighted the recurring merits of mixed micelles over single polymer micelles towards anticancer efficacy [12]. This review is mainly focused on the exploration of mixed micelle systems with a common denominator, which is that the combination of different types of polymers or the combination of a polymer and a biopolymer subserves the delivery of bioactive compounds or even operates as a prodrug system. Nanomanufacturing 2023, 3, 233–247. https://doi.org/10.3390/nanomanufacturing3020015 https://www.mdpi.com/journal/nanomanufacturing