Oxaborole-based polymers are stimuli-responsive materials that can reversibly interact with diols at pH values higher than their pK_a. The strong binding of the oxaborole with cis-hydroxyl groups allow rapid cross-linking of the polymer chains. In this study, we exploited this phenomenon to develop a novel delivery system for the complexation, protection, and delivery of epidermal growth factor receptors (EGFR) siRNA (small interfering RNA). Galactose and oxaborole polymers were first synthesized by the reversible addition–fragmentation chain transfer (RAFT) process, and they were found to show a robust interaction with each other via the oxaborole-diol effect, which allowed the formation of stable polyplexes with siRNA. Although complexes were successfully formed between the neutral galactose and oxaborole-based polymers, these complexes were insufficient in the protection of the siRNA. Therefore, cationic glycopolymers and oxaborole polymers were investigated showing superior complexation with siRNA and exhibiting effective gene silencing in HeLa (cervical) cancer cells, while showing low toxicity. Gene silencing of up to 60% was achieved with these new complexes in the presence and absence of serum. The excellent stability of the complexes under physiological conditions and the observed low cytotoxicity 48 h post-transfection demonstrated the high potential of this new system for gene silencing therapy application in clinics.

This report describes the compositional and structural design strategy of a zeolite-polymer composite nanofiber mesh for the efficient removal of uremic toxins towards blood purification application. The nanofiber is fabricated by electrospinning composite solution of biocompatible poly(ethylene-co-vinyl alcohol) (EVOH) and zeolite particles which are capable of selectively adsorbing uremic toxins such as creatinine. By controlling electrospinning conditions carefully, the incorporated zeolites in EVOH were found to correspond closely to the feed ratios. Elemental mapping images of Si show that zeolites were uniformly blended within the fibers. The fabricated composite fibers successfully adsorbed creatinine from solution and the adsorption capacity reached a maximum at 12 h. The crystallinity of the nanofiber was also controlled by varying the composition of ethylene content in EVOH. Less crystallinity resulted in higher creatinine adsorption capacity due to the barrier property of EVOH. Cytotoxicity assay demonstrated that the composite fibers showed less toxicity than free zeolite particles which killed more than 95% of cells. The proposed composite fibers, therefore, have the potential to be utilized as a new approach to removing creatinine selectively from the bloodstream.

Messenger RNA (mRNA) therapeutics have recently demonstrated high clinical potential with the accelerated approval of SARS-CoV-2 vaccines. For fulfilling the promise of unprecedented mRNA-based treatments, the development of safe and efficient carriers is still necessary to achieve effective delivery of mRNA. Herein, we prepared mRNA-loaded nanocarriers for enhanced in vivo delivery using biocompatible block copolymers having functional amino acid moieties for tunable interaction with mRNA. The block copolymers were based on flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) modified with glycine (Gly), leucine (Leu) or tyrosine (Tyr) via ester bonds to generate block catiomers. Moreover, the amino acids can be gradually detached from the block copolymers after ester bond hydrolyzation, avoiding cytotoxic effects. When mixed with mRNA, the block catiomers formed narrowly distributed polymeric micelles with high stability and enhanced delivery efficiency. Particularly, the micelles based on tyrosine-modified PEG-PG (PEG-PGTyr), which formed polyion complex (PIC) and π–π stacking with mRNA, displayed excellent stability against polyanions and promoted mRNA integrity in serum. The PEG-PGTyr-based micelles also increased the cellular uptake and the endosomal escape, promoting high protein expression both in vitro and in vivo. Furthermore, the PEG-PGTyr-based micelles significantly extended the half-life of the loaded mRNA after intravenous injection. Our results highlight the potential of PEG-PGTyr-based micelles as safe and effective carriers for mRNA, expediting the rational design of polymeric materials for enhanced mRNA delivery. Graphical abstract

Indoleamine 2,3-dioxygenase (IDO) is an immunomodulating enzyme that is overexpressed in many cancers with poor prognosis. IDO suppresses T cell immunity by catabolizing tryptophan into kynurenine (KYN), which induces apoptosis in T effector cells and enhances T regulatory cells, providing a powerful immunosuppressive mechanism in tumors. Thus, major efforts for developing IDO inhibitors have been undertaken. Among them, 1-Methyl-l-Tryptophan (MLT) and 1-Methyl-d-Tryptophan (MDT) effectively inhibit IDO in preclinical tumor models and the latter is under clinical evaluation. However, both MLT and MDT present poor pharmacokinetics, with the maximum serum concentration being below their 50% inhibitory concentration value. Herein, we have developed polymeric IDO inhibitors based on MLT, which can release active MLT after enzymatic degradation, toward establishing superior antitumor immunotherapies. These polymers were prepared by ring opening polymerization of an N-phenyl carbamate (NPC) derivative of MLT that was synthesized by carbamylation with diphenyl carbonate. By using ω-amino-poly(ethylene glycol) (PEG-NH₂) as the macroinitiator, we prepared amphiphilic PEG-poly(MLT) block copolymers, which self-assembled into polymeric micelles in aqueous conditions. The PEG-poly(MLT) block copolymers could be readily degraded by chymotrypsin and the micelles were able to reduce the levels of KYN in activated macrophages. These results provide a strong rationale for pursuing MLT-based polymeric micelles as tumor-targeted prodrug systems.