We herein demonstrate the outstanding protein-repelling characteristic of starlike micelles and polymersomes manufactured from amphiphilic block copolymers made by poly(butylene oxide) (PBO) hydrophobic segments and polyglycidol (PGL) hydrophilic outer shells. Although positively charged proteins (herein modeled by lysozyme) may adsorb onto the surface of micelles and polymersomes where the assemblies are stabilized by short PGL chains (degree of polymerization smaller then 15), the protein adsorption vanishes when the degree of polymerization of the hydrophilic segment (PGL) is higher than ~ 20, regardless the morphology. This has been probed by using three different model proteins which are remarkable different concerning molecular weight, size and zeta potential (bovine serum albumin -BSA, lysozyme and immunoglobulin G -IgG). Indeed, the adsorption of the most abundant plasma protein (herein modeled as BSA) is circumvented even by using very short PGL shells due to the highly negative zeta potential of the produced assemblies which presumably promotes protein-nanoparticle electrostatic repulsion. The highly negative zeta potential, on the other hand, enables lysozyme adsorption and the phenomenon is governed by electrostatic forces as evidenced by isothermal titration calorimetry.Nevertheless, the protein coating can be circumvented by slightly increasing the degree of polymerization of the hydrophilic segment. Notably, the PGL length required to circumvent protein fouling is significantly smaller than the one required for PEO. This feature and the safety concerns regarding the synthetic procedures on the preparation of poly(ethylene oxide)-based amphiphilic copolymers might make polyglycidol a promising alternative towards the production of non-fouling particles.

Background: Gene delivery is a promising technology for treating diseases linked to abnormal gene expression. Since nucleic acids are the therapeutic entities in such approach, a transfecting vector is required because the macromolecules are not able to efficiently enter the cells by themselves. Viral vectors have been evidenced to be highly effective in this context; however, they suffer from fundamental drawbacks, such as the ability to stimulate immune responses. The development of synthetic vectors has accordingly emerged as an alternative. Objectives: Gene delivery by using non-viral vectors is a multi-step process that poses many challenges, either regarding the extracellular or intracellular media. We explore the delivery pathway and afterwards, we review the main classes of non-viral gene delivery vectors. We further focus on the progresses concerning polyethylenimine-based polymer-nucleic acid polyplexes, which have emerged as one of the most efficient systems for delivering genetic material inside the cells. Discussion: The complexity of the whole transfection pathway, along with a lack of fundamental understanding, particularly regarding the intracellular trafficking of nucleic acids complexed to non-viral vectors, probably justifies the current (beginning of 2021) limited number of formulations that have progressed to clinical trials. Truly, successful medical developments still require a lot of basic research. Conclusion: Advances in macromolecular chemistry and high-resolution imaging techniques will be useful to understand fundamental aspects towards further optimizations and future applications. More investigations concerning the dynamics, thermodynamics and structural parameters of polyplexes would be valuable since they can be connected to the different levels of transfection efficiency hitherto evidenced.

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Self-assembled bilayer structures such as those produced from amphiphilic block copolymers (polymersomes) are potentially useful in a wide array of applications including the production of artificial cells and organelles, nanoreactors, and delivery systems. These constructs are of important fundamental interest, and they are also frequently considered toward advances in bionanotechnology and nanomedicine. In this framework, membrane permeability is perhaps the most important property of such functional materials. Having in mind these considerations, we herein report the manufacturing of intrinsically permeable polymersomes produced using block copolymers comprising poly­[2-(diisopropylamino)-ethyl methacrylate] (PDPA) as the hydrophobic segment. Although being water insoluble at pH 7.4, its pK a(PDPA) ∼ 6.8 leads to the presence of a fraction of protonated amino groups close to the physiological pH, thus conducting the formation of relatively swollen hydrophobic segments. Rhodamine B-loaded vesicles demonstrated that this feature confers inherent permeability to the polymeric membrane, which can still be modulated to some extent by the solution pH. Indeed, even at higher pH values where the PDPA chains are fully deprotonated, the experiments demonstrate that the membranes remain permeable. While membrane permeability can be, for instance, regulated by introducing membrane proteins and DNA nanopores, examples of membrane-forming polymers with intrinsic permeability have been seldom reported so far, and the possibility to regulate the flow of chemicals in these compartments by tuning block copolymer features and ambient conditions is of due relevance. The permeable nature of PDPA membranes possibly applies to a wide array of small molecules, and these findings can in principle be translocated to a variety of disparate bio-related applications.

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