Biomacromolecules最新文献

The major challenges in cancer chemotherapy are the severe side effects of the chemotherapeutic drugs due to their off-target toxicity to normal cells. Peptide amphiphiles capable of enzyme-instructed intracellular self-assembly have emerged as biocompatible alternatives, yet achieving high cancer selectivity remains challenging. Herein, we reported a dual enzyme-responsive zwitterionic peptide assembly, which undergoes matrix metalloproteinase induced-disassembly and cathepsin B instructed-assembly to form the fiber in the cancerous lysosome. This sequential enzymatic process induces lysosomal membrane permeabilization and cancer cell death at low micromolar concentrations while remaining inactive in normal cells lacking these enzymes. As a result, very high cancer selectivity (cancer selectivity index of 64.1) is achieved with our designed peptide amphiphiles. The peptide amphiphile also shows significant tumor regression with low doses and no in vivo toxicity tested in the human colorectal adenocarcinoma cell line (HT-29) xenograft tumor model.

Phosphatidylcholine and its derivatives are highly attractive for their ability to enhance both the circulation stability and the cellular uptake of drug carriers. However, the mechanism underlying the phospholipid surface function and the impact of phospholipid density on micelle performance remain poorly understood. Here, we report the synthesis of a series of novel linear-dendritic copolymers based on phosphatidylcholine-polycaprolactone, where varying amounts of phosphatidylcholine groups can be attached to a single junction point at one end of the polycaprolactone. These copolymers self-assemble in aqueous solution to form micelles with different morphologies, demonstrating improved stability, drug loading capacity, and release behaviors with an increasing phospholipid content. Importantly, the micelles exhibit selective cellular uptake with a significant phospholipid dose dependence and show excellent antitumor efficacy in vivo at low drug dosages. This work provides a facile approach to designing and preparing nonlinear phospholipid copolymers with branched topology, offering a promising platform for drug delivery applications.

Tissue adhesive patches are widely favored for their easy application, efficient wound closure, and ability to avoid secondary damage. However, postoperative repair of vital organs (e.g., the liver) requires materials with synchronous wound sealing, hemostasis, and antiadhesion functions. A biodegradable Janus Adhesive Tissue Patch (JATP) with three functional layers (antiadhesive, reinforceable, and adhesive) was fabricated. The component of the adhesive layer is a triblock copolymer prepared via free radical polymerization; poly-d,l-lactide-co-glycolide served as the antiadhesive layer, and Pluronic F127 as the middle layer to optimize mechanical properties and toughness. The adhesive layer formed strong covalent and hydrogen bonds with tissues, reaching an adhesion strength of >30 kPa and burst pressure of up to 60 kPa. JATP rapidly absorbed tissue moisture to form a hemostatic gel for effective sealing and hemostasis. In vivo tests confirmed its rapid adhesion, hemostasis, biodegradability, and biocompatibility, suggesting JATP is a promising biomaterial for postoperative repair with broad clinical potential.

Nanostructured materials are promising substrates for biocatalyst immobilization. We report a green and sustainable strategy for enzyme immobilization using cellulose nanocrystals (CNCs) derived from renewable sources. CNCs offer biodegradability, low toxicity, and high surface area, enabling efficient immobilization of Candida rugosa lipase (CRL). Covalent bioconjugation on TEMPO-oxidized cellulose nanocrystals (TO_CNCs) provides an almost quantitative immobilization yield without releasing toxic byproducts, but with reduced enzymatic activity per mg of immobilized protein. Conversely, nonspecific immobilization on sulfated cellulose nanocrystals (S_CNCs) shows very low immobilization yield but preserves enzyme mobility and slightly enhances activity. The immobilized biocatalysts were characterized by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, high-resolution synchrotron X-ray diffractometry (XRD), ultraviolet-visible spectroscopy (UV-vis), field emission scanning electron microscopy (FE-SEM), bicinchoninic acid assay (BCA), solid-state nuclear magnetic resonance (ssNMR) spectroscopy, and enzymatic activity measurements. Notably, ssNMR reveals the effectiveness of TO_CNCs in preventing enzyme dispersion.

Effective gas-chemotherapy requires the synchronized intratumoral release of therapeutic agents, which is hindered by physiological barriers and unsynchronized delivery. Herein, we address this hurdle by covalently conjugating doxorubicin (DOX) to polymer backbones via trisulfide bonds. This bond cleaves specifically in the high-glutathione tumor microenvironment, triggering simultaneous release of DOX and H₂S. The optimal random copolymer, PCB₆₁-3S₂₈-D₁₀ with the polymerization degrees of 61, 28, and 10 for poly(carboxybetaine methacrylate) (PCB), trisulfide-containing segments, and DOX amount, respectively, can self-assemble into stable micelles and exhibit minimal protein adsorption for efficient tumor accumulation. PCB₆₁-3S₂₈-D₁₀ shows enhanced cytotoxicity with an IC₅₀ of 2.16 μg mL^-1, which is a 2-fold increase in potency compared with free DOX. PCB₆₁-3S₂₈-D₁₀ achieves a remarkable in vivo tumor inhibition rate of 87.9%, significantly surpassing free DOX and the comparable disulfide bond-containing group. This study underscores the potential of trisulfide-bridged zwitterionic nanocarriers as a robust platform for synchronized gas-chemotherapy.

Hyperuricemia, caused by purine metabolism disorders, is associated with gout, kidney stones, and cardiovascular disease. While urate oxidase (UOX) therapy reduces uric acid by converting it to allantoin, the generation of hydrogen peroxide (H₂O₂) limits its safety and efficacy due to oxidative stress. To overcome this limitation, we developed a modular enzyme assembly that colocalizes UOX with catalase (CAT), an H₂O₂-degrading enzyme, via engineered coiled-coil motifs. Complementary motifs bearing site-specific cysteine residues were designed to promote disulfide-stabilized heterodimerization, and their binding specificity and affinity were validated using a fluorescence-based assay. These motifs were then fused to UOX and CAT to enable spontaneous and stable assembly of a functional enzyme complex without chemical conjugation. The resulting complex exhibited high catalytic efficiency and significantly reduced reactive oxygen species-mediated cytotoxicity in human colon carcinoma cells. This work provides a tunable strategy for dual-enzyme assembly, enhancing therapeutic synergy while minimizing oxidative side effects in hyperuricemia treatment.

Biodegradable nerve guidance conduits (NGCs) are compelling alternatives to autografts for repairing severe peripheral nerve injuries. However, a major obstacle in developing effective NGCs is their structural and functional mismatch with repair and regeneration, leading to inadequate neuronal guidance and improper axon dispersion. Herein, we report a biomimetic NGC that replicates the multiscale architecture of native nerves. It features aligned microchannels of clinically relevant lengths and nanotextured walls. The biomimetic topology is fabricated in poly(l-lactic acid) (PLLA) via an integrated forming technique that exploits strain-induced crystallization to control crack propagation. Comprehensive in vitro experiments confirm the exceptional thermal stability, mechanical robustness, and structural integrity of PLLA NGCs. Importantly, the synergistic micro- and nanoscale alignment is critical for directing axon growth and minimizing dispersion. By elucidating this novel fabrication mechanism and demonstrating dual-scale bioinspired architecture, our work establishes a new platform with the potential for large-gap peripheral nerve repair.

Fast-acting adhesives that bind underwater are needed for many applications. Complex coacervates, viscous, hydrated phase-separated materials, have recently shown much promise as adhesives that can be used in wet environments. Here, negative polyelectrolytes, poly(styrenesulfonate), PSS, and poly(acrylamidomethylpropanesulfonate), PAMPS, were complexed with the positively charged antibiotics neomycin and streptomycin. Opposite charges on these components pair, yielding materials that have ideal viscoelastic properties for use in pressure-sensitive "instant" adhesion in aqueous environments. PSS complexed with neomycin or mixtures of neomycin and streptomycin were about 20 °C above their glass transition temperatures at physiological use conditions (0.15 M NaCl and 37 °C) and provided up to 100 kPa and 80 J m^-2 of adhesion strength and energy, respectively, at low strain rates. Underwater adhesion was observed on both hydrophilic surfaces, such as glass and metal, and hydrophobic surfaces, such as rubber. Although the antibiotic building blocks carried a low charge of 3+ or 6+, the interactions between their protonated amines and the aromatic sulfonate groups of the PSS were strong enough to provide stability, or salt resistance, against NaCl solutions with concentrations up to 1.7 M. An analysis of the equilibrium complexation (liquid-liquid phase separation) of small ligands with long polyelectrolytes showed how the salt resistance depends on the solution concentration of the ligand and how a sustained release mechanism is therefore built into these complex coacervates, allowing the antibiotics to kill Gram-positive and Gram-negative bacteria. Quantitative NMR measurements of buffered solutions of 0.15 M NaCl above the coacervates showed gradual release of antibiotics without significant release of the polyelectrolyte. This work introduces the use of underwater bioactive instant adhesive coacervates with competitive properties that are made from a polyelectrolyte and a small molecule.

Tumor chemoresistance caused by P-glycoprotein (P-gp) expression in cancer cells remains a significant challenge in cancer chemotherapy. Herein, a novel P-gp-inhibiting lopinavir derivative (LD) was synthesized via esterification of protease inhibitor lopinavir with 5-methyl-4-oxohexanoic acid. LD proved to be a potent P-gp inhibitor with EC₅₀ ∼ 1 μM, capable of considerable sensitization of P-gp-expressing cancer cells to conventional cytostatic drugs in vitro. The oxo functional group introduced in LD allowed its covalent linkage with the N-(2-hydroxypropyl)methacrylamide copolymer carrier via a pH-sensitive hydrazone bond (P-LD). Polymer conjugation enhanced the pharmacological properties of LD in vivo, increasing its half-life in the bloodstream, protecting it from metabolic degradation, and promoting its accumulation in tumors via the enhanced permeability and retention effect. P-LD exhibited P-gp-inhibitory activity and sensitized cells to polymer-bound cytostatic drugs in vitro. Importantly, P-LD remarkably improved the antitumor efficacy of a polymer-bound doxorubicin in two P-gp-expressing mouse tumor models without exhibiting any systemic toxicity.

Cellulose, the most abundant renewable biobased polymer on Earth, is renowned for its biodegradability, low toxicity, and excellent mechanical properties. As dielectric materials increasingly move toward green and sustainable development, cellulose and its derivatives have emerged as promising alternatives. However, their dielectric properties depend mainly on microstructure, crystallinity, and aggregation state, which vary notably across cellulose matrices. This review first outlines the fundamental mechanisms of dielectric energy storage, highlighting cellulose structure's role in regulating key performance parameters. It then analyzes the structure-dielectric property relationship of cellulose and its derivatives, focusing on molecular arrangement, intermolecular interactions, and aggregation. Further, it reviews recent advances in three preparation strategies (molecular design, functional filler incorporation, multilayer construction), emphasizing their regulation mechanisms and advantages. Finally, it discusses limitations, challenges, and future trends. This review aims to provide references for the development of cellulose-based dielectric materials toward practical applications in flexible electronics and energy storage systems.