Biomacromolecules最新文献

RALA is an amphipathic cationic peptide demonstrated to be a low-toxicity and high-efficiency delivery platform for the systemic delivery of nucleic acid therapeutics. This work reports three RALA-derived peptides modified with N-terminal palmitic acid, engineered through amino acid substitutions and truncated sequences. All three peptides have good nucleic acid encapsulation, release and uptake, biocompatibility, and endolysosome escape. The siRNA transfection efficiency is about 90%, and the silencing rate of GA (C16-GLFWHHHARLARALARHLARALRA) exceeds that of lipofectamine 2000 (siRNA concentration = 50 nM). Truncating the peptide chain while retaining a certain amount of arginine ensures an effective particle size. Replacing glutamic acid with three histidines ensures an effective zeta potential and accelerates the endosome escape process through the proton sponge phenomenon. Introducing phenylalanine enhances the carrier-cell interaction. We believe that they are powerful carriers of siRNA therapy and may have good application prospects in treating various diseases.

Biomolecular condensates are distinct subcellular structures with on-demand material states and dynamics in living cells. However, strategies for modulating their material states and physicochemical properties are lacking. Here, we report a chemical strategy for modulating the condensate states of intrinsically disordered proteins in bacterial Escherichia coli cells. This is achieved by noncanonical amino acid (DOPA) incorporation into model resilin-like proteins (RLPs) to endow autonomous oxidative and coordinative cross-linking mechanisms. Biogenesis of spherical gel-like condensates is achieved upon heterologous expression of the DOPA-incorporated RLP in the cells at 30 °C. We reveal that liquid-liquid phase separation underlies the formation of liquid condensates, and this liquid-like state is metastable and its dynamics is compromised by the oxidative and coordinative cross-linkings that ultimately drive the liquid-to-gel transition. Therefore, this study has deepened our understanding of biomolecular condensation and offers a new chemical strategy to expand the landscape of condensation phenotypes of living cells.

Supramolecular peptide hydrogels (SPHs) consist of peptides containing hydrogelators and functional epitopes, which can first self-assemble into nanofibers and then physically entangle together to form dynamic three-dimensional networks. Their porous structures, excellent bioactivity, and high dynamicity, similar to an extracellular matrix (ECM), have great potential in artificial ECM. The properties of the hydrogel are largely dependent on peptides. The noncovalent interactions among hydrogelators drive the formation of assemblies and further transition into hydrogels, while bioactive epitopes modulate cell-cell and cell-ECM interactions. Therefore, SPHs can support cell growth, making them ideal biomaterials for ECM mimics. This Review outlines the classical molecular design of SPHs from hydrogelators to functional epitopes and summarizes the recent advancements of SPHs as artificial ECMs in nervous system repair, wound healing, bone and cartilage regeneration, and organoid culture. This emerging SPH platform could provide an alternative strategy for developing more effective biomaterials for tissue engineering.

This study explores the synthesis and application of artificial zymogens using protein-polymer hybrids to mimic the controlled enzyme activation observed in natural zymogens. Pro-trypsin (pro-TR) and pro-chymotrypsin (pro-CT) hybrids were engineered by modifying the surfaces of trypsin (TR) and chymotrypsin (CT) with cleavable peptide inhibitors utilizing surface-initiated atom transfer radical polymerization. These hybrids exhibited 70 and 90% reductions in catalytic efficiency for pro-TR and pro-CT, respectively, due to the inhibitory effect of the grafted peptide inhibitors. The activation of pro-TR by CT and pro-CT by TR resulted in 1.5- and 2.5-fold increases in enzymatic activity, respectively. Furthermore, the activated hybrids triggered an enzyme activation cascade, enabling amplification of activity through a dual pro-protease hybrid system. This study highlights the potential of artificial zymogens for therapeutic interventions and biodetection platforms by harnessing enzyme activation cascades for precise control of catalytic activity.

In situ gelling eye drops of tacrolimus (FK506 Gel) were developed to address the formulation challenge of tacrolimus for anterior ocular inflammatory diseases. Both in silico and in vitro investigations were conducted to screen a suitable cyclodextrin species to increase the drug solubility. Guanosine was employed as the gelator and combined with inclusion complexes of tacrolimus in the presence of borate anions to obtain FK506 Gel, which gelated when came into contact with cations in tear fluid and led to the formation of a nanofibrous hydrogel. The versatility of our design to improve the solubility and ocular retention of the hydrophobic drug was demonstrated in vivo with coumarin 6 as a model drug. A mouse dry eye model was used to evaluate the therapeutic effects of FK506 Gel, which, in combination with the biocompatibility study, suggested that FK506 Gel served as a superior treatment for anterior ocular inflammatory diseases.

We synthesize four series of novel biodegradable poly(alkylene succinate-ran-caprolactone) random copolyesters using a two-step ring-opening/transesterification and polycondensation process with ε-caprolactone (PCL) as a common comonomer. The second comonomers are succinic acid derivatives, with variations in the number of methylene groups (n_CH2) in the glycol segment, n_CH2 = 2, 4, 8, and 12. The obtained copolyesters were poly(ethylene succinate-ran-PCL) (ES_xCL_y), poly(butylene succinate-ran-PCL) (BS_xCL_y), poly(octamethylene succinate-ran-PCL) (OS_xCL_y), and poly(dodecylene succinate-ran-PCL) (DS_xCL_y). We discovered a new mixed isodimorphic/comonomer exclusion crystallization in ES_xCL_y copolymers. The BS_xCL_y, OS_xCL_y, and DS_xCL_y copolymers display isodimorphic behavior. Our findings revealed a significant variation in the pseudoeutectic point position, from mixed isodimorphism/comonomer exclusion crystallization to isodimorphism with pseudoeutectic point variation from 54% to up to 90%. Moreover, we established a link between the melting temperature depression slope variation and the comonomer inclusion/exclusion balance, providing valuable insights into the complex topic of isodimorphic random copolymers.

Peptides and their conjugates are appealing as molecular scaffolds for constructing supramolecular biomaterials from the bottom up. Through strategic sequence design and interaction modulation, these peptides can self-assemble into diverse nanostructures that can, in turn, mimic the structural and catalytic functions of contemporary proteins. Here, inspired by the histidine brace active site identified in the metalloenzyme, we developed a triblock polypeptide with a hydrophobic polyleucine segment, a hydrophilic polylysine segment, and a terminal oligohistidine segment. This polypeptide demonstrates tunable and adaptive self-assembly morphologies. Moreover, copper ions can interact with the oligohistidine chelator and mediate the supramolecular assembly, generating metal-ligand centers for redox flow. The triblock polypeptide-based peptide micelles show Fenton-type activity with high substrate affinity when coassembled with copper ions. We have also engineered therapeutic micelles by coassembling two polypeptides, one integrated with copper ions and the other conjugated with glucose oxidase. This coassembled nanoplatform shows high in vitro and in vivo antitumor efficacy through a mechanism that combines triggered starvation and chemodynamic therapy. The versatility of this polypeptide sequence, which is compatible with various metal ions and functional ligands, paves the way for a broad spectrum of therapeutic and diagnostic applications.

We explore the reentrant condensation of polyelectrolytes triggered by multivalent salts, whose phase-transition mechanism remains under debate. We propose a theory to study the reentrant condensation, which separates the electrostatic effect into two parts: a short-range electrostatic gluonic effect because of sharing of multivalent ions by ionic monomers and a long-range electrostatic correlation effect from all ions. The theory suggests that the electrostatic gluonic effect governs reentrant condensation, requiring a minimum coupling energy to initiate the phase transition. This explains why diluted salts with selective multivalency trigger a polyelectrolyte phase transition. The theory also uncovers that strong adsorption of multivalent ions onto ionic monomers causes low-salt concentrations to induce both collapse and reentry transitions. Additionally, we highlight how the incompatibility of uncharged polyelectrolyte moieties with water affects the polyelectrolyte phase behaviors. The obtained results will contribute to the understanding of biological phase separations if multivalent ions bound to biopolyelectrolytes play an essential role.

To address the adverse reactions caused by the implantation of blood-contacting materials, researchers have developed different strategies, of which mimicking multiple key features of endothelial cells is the most effective. However, simultaneously immobilizing multiple chemical components on a single material surface and maintaining the effects of individual components are challenging. In this work, endothelium-mimicking silicone surfaces were developed by incorporating the antifouling polymer poly(oligo(ethylene glycol) methacrylate), the glycosaminoglycan analog poly(sodium 4-vinyl-benzenesulfonate) and a nitric oxide catalyst (selenocystamine dihydrochloride). Through the rational regulation of multiple chemical components, the surfaces harmoniously resisted nonspecific protein adsorption, platelet adhesion and activation and smooth muscle cell hyperproliferation while promoting endothelial cell proliferation and migration. The coculture experiment with HUVECs and HUVSMCs showed that the optimum selectivity of HUVECs/HUVSMCs was ∼1.7. This work contributes insight into the control of antifouling properties and endothelial selectivity, providing a new avenue for the development of blood-contacting materials.

This study found that the sources of cellulose have a significant effect on the parameters related to the kinks present in nanocellulose. During nanocellulose preparation, 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO)-mediated oxidation induced partial depolymerization on whole cellulose and made the amorphous regions more susceptible to consequent mechanical treatment irrespective of cellulose sources. However, plant cellulose microfibrils were prone to break into shorter nanocellulose with fewer kinks, while bacterial and tunicate cellulose were more likely to bend rather than break, thus leading to the generation of more kinks. The kinks did not show significant effects on the size, crystallinity index, and thermal properties of nanocellulose for each cellulose source, though the kink numbers were positively related to the mechanical performance of nanocellulose. Collectively, this study elucidated the kink formation mechanisms and clarified the effects of kinks on nanocellulose performance, thus providing new insights into understanding the source and behaviors of microdefects present in nanocellulose.