Programmed release of small molecular drugs from polymersomes is of great importance in drug delivery. A significant challenge is to adjust the membrane permeability in a well-controlled manner. Herein, we propose a strategy for controlling membrane phase separation by photo-cross-linking of the membrane-forming blocks with different molecular architectures. We synthesized three amphiphilic block copolymers with different membrane-forming blocks, which are poly(ethylene oxide)₄₃-b-poly((ε-caprolactone)₄₅-stat-((α-(cinnamoyloxymethyl)-1,2,3-triazol)caprolactone)₂₅) (PEO₄₃-b-P(CL₄₅-stat-CTCL₂₅)), PEO₄₃-b-P(CL₁₀₈-stat-CTCL₁₆), and PEO₄₃-b-PCTCL₄-b-PCL₇₉. These polymers were self-assembled into polymersomes using either a solvent-switch or powder rehydration method, and the obtained polymersomes were characterized by dynamic light scattering and transmission electron microscopy. Then the phase separation patterns within the polymersome membranes were investigated by mesoscopic dynamics (MesoDyn) simulations. To further confirm the change of the membrane permeability that resulted from the phase separation within the membrane, doxorubicin, as a small molecular drug, was loaded and released from the polymersomes. Due to the incompatibility between membrane-forming moieties (PCTCL and PCL), phase separation occurs and the release rate can be tuned by controlling the membrane phase pattern or by photo-cross-linking. Moreover, besides the compacting effect by formation of chemical bonds in the membrane, the cross-linking process can act as a driving force to facilitate the rearrangement and re-orientation of the phase pattern, which also influences the drug release behavior by modulating the cross-membrane distribution of the amorphous PCTCL moieties. In this way, the strategy of focusing on the membrane phase separation for the preparation of the polymersomes with finely tunable drug release rate can be envisioned and designed accordingly, which is of great significance in the field of delivery vehicles for programmed drug release.

Synthetic poly(amino acid)s with good biodegradable and biocompatible properties have attracted increased attention as carriers in biomedical applications in recent years, their synthesis and purification procedures are usually complicated and some by-products would occur yet. Given this, polypeptide with good biodegradable and biocompatible properties is prepared and optimized by one-step and direct synthesis strategy and poly(valine) (PVal) is selected here as a model polypeptide in this study. This newly generated PVal can self-assemble into poly(valine) nanoparticles (PVal-NPs) with a high drug-loading capacity (>20 wt%) of doxorubicin (DOX) and shows strong cytotoxicity against 4T1 cells. Upon cellular internalization, the release of DOX could be accelerated by the endosomal acidic environment which leads to enhanced anticancer effects. The resultsin vivo show that DOX@PVal-NPs have a long blood circulation time, high cancer accumulation and penetration, and good therapeutic performance in 4T1 tumor-bearing mice without causing obvious adverse effect on main organs. With these combined advantages, these PVal-based nanoplatform would provide an effective drug delivery tool for clinical breast cancer therapy.

Copolymerization of propylene oxide (PO)/carbon dioxide (CO₂) and lactide (LA) is achievable to form new copolymers, combining the advantages of both poly(propylene carbonate) (PPC) and polylactide (PLA). In this study, we designed a dinuclear Salen-Cr(III) complex, which showed higher efficiency for copolymerization of PO/CO₂ and LA than that of mononuclear Salen-Cr(III) complex. Besides, we successfully obtained gradient and random copolymers of PPC-PLA in one pot. Furthermore, by adjusting reaction temperature, block ratios of PPC/PLA in copolymers were controllable (block ratio of PPC/PLA=1.0 at 40 °C, while block ratio of PPC/PLA=0.5 at room temperature). While increasing the reaction temperature to 60 °C, conversion of LA was much faster than that of PO so that gradient copolymers were obtained.

Oligonucleotide therapeutics have great potential to target the currently undruggable genes and to generate entirely new therapeutic paradigms in multiple types of disease, thus having attracted much attention in recent years. However, their applications are greatly hindered by a lack of safe and efficient oligonucleotide-delivery vectors. Polyplex nanovesicles formed from oligonucleotides and the cationic block have shown exceptional features for the delivery of therapeutic oligonucleotides and other biopharmaceuticals. Nevertheless, these polyplex nanovesicles are deeply fraught with difficulty in tolerating physiological ionic strength. Inspired by the high binding ability between the dipicolylamine (DPA)/zinc(II) complex and the phosphodiester moieties of oligonucleotides, herein, we designed a coordinative cationic block to solve the intrinsic stability dilemma. Moreover, we found the stability of the resulted polyplex nanovesicles could be easily tuned by the content of coordinated zinc ions. In vitro cellular studies implied that the prepared zinc(II)-coordinative polyplex nanovesicles preferred to retain in the lysosomes upon internalization, making them ideal delivery candidates for the lysosome-targeting oligonucleotide therapeutics.

Liquid-liquid phase separation (LLPS) or biomolecular condensation that leads to formation of membraneless organelles plays a critical role in many biochemical processes. Mechanism study of regulating LLPS is therefore central to the understanding of protein aggregation and disease-relevant process. We report a fused in sarcoma protein (FUS)-derived low complexity (LC) sequence that undergoes LLPS in the presence of metal ions. The LC protein was constructed by fusing a hexhistidine-tag to the N-terminal low complexity domain (the residues 1–165 in QGSY-rich segment) of FUS. Spontaneous condensation of the intrinsic disordered protein into coacervate droplets was observed in the presence of metal ions that chelate oligohistidine moieties to form protein matrix. We demonstrate the key role of metal ion-histidine coordination in governing LLPS behaviours and the fluidity of biomolecular condensates. By taking advantage of competitive binding using chelators, we show the possibility of regulating dynamic behaviors of disease-relevant protein droplets, and developing a potential approach towards controllable biological encapsulation/release.

Owing to the significant importance in clinics, antibacterial activity is thought as one indispensable feature of the next generation of absorbable sutures. It is challenging but imperative to arm the existing absorbable sutures with antibacterial functions. The present study describes a "gradient deposition" technique to coat a continuous and smooth layer of chitosan on the surface of absorbable sutures. Specifically, chitosan solution is arranged to undergo gradient pH decline step by step while during each pH interval, the solution is allowed to stand for a predetermined period of time in order to control gradual chitosan deposition. Chitosan nanoparticles are found to be first generated on suture surface and finally developed into a smooth chitosan layer as the antibacterial surface. In vitro and in vivo results demonstrated that coating chitosan on sutures by our technique could relieve wound inflammation, stimulate collagen deposition, regenerate blood vessels, and assist tissue repairing, consequently leading to a significant enhancement of wound healing effect. This technique is highlighted with low cost, extreme convenience and excellent safety without organic solvents. Furthermore, the "gradient deposition" technique would not affect the fundamental properties of matrix and thus hold promises as a universal way for superficial antibacterial modification towards almost all the surgical implanted materials, including but not limited to absorbable sutures.

After repeated frustrations with amyloid beta (Aβ)-targeted clinical trials for Alzheimer’s disease (AD) in recent years, the therapeutic focus of AD has gradually shifted from Aβ to tau protein. The misfolding and aggregation of tau protein into neurofibrillary tangles (NFTs) cause neuron death and synaptic dysfunction, and the deposition of NFTs is more closely related to the severity of AD than Aβ plaques. Thus, it has great potential to target tau protein aggregation for AD treatment. The hexapeptide VQIVYK (known as PHF6) in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors. Here, inspired by natural heat shock protein (HSPs), we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle (MSPM) as a novel tau-targeted AD therapy. With tunable phase-separated microdomains on the surface, the nanochaperone could effectively bind with PHF6 aggregates, inhibit PHF6 aggregation, block neuronal internalization of PHF6 species, thus significantly alleviating PHF6 mediated neurotoxicity. Moreover, the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates. This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.

RNA interference (RNAi), known for the highly efficient targeted gene silencing, has been demonstrated to be a promising means for cancer treatment. Meanwhile, an effective approach for siRNA delivery is urgently needed to meet the needs for its clinical application. Herein, we constructed a polymeric vector labeled with superparamagnetic iron oxide (SPIO) for magnetic resonance imaging (MRI) visible siRNA delivery. EGFR antibody was also modified to the surface of nanodrug to enhance the delivery effect. Our results showed that the vector exhibited great siRNA complexation ability and mediated an increased endocytosis of siRNA without obvious cytotoxicity. Besides, bothin vitro and in vivo studies evidenced the vector could effectively deliver siRNA into tumor cells, exert highly interfering effect, and show potent MR imaging capacity. The study provides a promising MRI-visible and EGFR targeting delivery system to improve RNAi efficacy for cancer therapy.

Mesenchymal stem cells (MSCs) have attracted great attention as a source of cells for regenerative medicine owing to their self-renewal ability and multiple differentiation potential. However, the serious shortage of MSCs and the difficulty of maintaining the differentiation potential during culture in vitro limit their application. Microcarrier culture technology is an effective method to realize large-scale culture of MSCs, whereas the effect of microcarriers properties on MSCs proliferation and differentiation potential maintenance should be investigated. In this study, Konjac glucomannan (KGM) microcarriers with a wide range of rigidity from 0.2 MPa to 10 MPa were prepared using water-in-oil emulsion polymerization. It was found that the microcarriers rigidity had great influence on MSCs by regulating cell spreading rate. Rapid proliferation and good differentiation potential maintenance of MSCs were achieved on the intermediate rigidity about 2.51±0.65 MPa with the faster spreading rate of cells. As a result, MSCs on 2.51±0.65 MPa KGM microcarriers proliferated about 27 times, which was 1.7 times as much as MSCs cultured on the commercial microcarriers Cytodex-1. The differentiation potential was also improved about 3.2 times compared to Cytodex-1. Therefore, it is indispensable to regulate microcarriers rigidity, especially for application of MSCs.

As a frontier imaging technique for biomedical applications, photoacoustic (PA) imaging has been developed rapidly. The development of new design strategies and excellent PA imaging reagents to boost PA conversion is eagerly desirable for high quality PA imaging but complicated to realize. Herein, we develop a new strategy in which PA imaging reagents with better properties can be easily optimized by polymerization. A series of new PA imaging reagents were designed and synthesized. The polymerization strategy can effectively promote the PA signal by specifically increasing the thermal-to-acoustic conversion efficiency. As these materials shared the same building units, the optimized effectiveness of polymerization strategy in terms of near-infrared light-harvesting capacity and thermal-to-acoustic conversion efficiency are discussed, rationally. The polymers with intense intramolecular motion exhibit an amplified PA signal by elevating thermal-to-acoustic conversion and its higher light-harvesting capability at redshifted region. The simultaneously strong PA signal and photothermal conversion efficiency of p-TTmB NPs enable precise PA imaging and effective photothermal therapy. This work highlights a simple and available design guideline of polymerization for amplifying the PA effect and optimizing existing materials.

Uveitis is a sophisticated syndrome showing a high relevance with reactive oxygen species (ROS). Herein, an ROS-responsive PEGylated polypeptide based macromolecular prodrug of herbaceous antioxidant ethyl caffeate (EC) is designed via phenylboronic esters with improved solubility for the alleviation of uveitis. The antioxidative 4-hydroxybenzyl alcohol (HBA) and EC can be released from the macromolecular EC prodrug under the stimulation of ROS, which can effectively protect cells against oxidative stress-induced injury in an ROS-depletion way. The antioxidative and protective effects of the macromolecular EC prodrug in vivo are further verified in a uveitis mouse model. Overall, this work not only provides a handy method to synthesize a phenylboronic ester-bearing EC prodrug which is highly sensitive to pathological ROS, but also depicts a promising future to apply macromolecular antioxidative prodrugs in the treatment of uveitis as well as other ROS-related diseases.

Commercial tissue adhesives have been widely applied in wound hemostats and dressings while enhancing the hemostasis and healing capabilities is challenging to meet clinical needs. Herein, we designed the glucose- and catechol-functionalized derivatives from commercial ε-polylysine (EPL) and prepared the hydrogels by simple amidation and catechol-crosslinking reactions, which have larger swelling ratios of 220%−240%, suitable microporous size of about 6−8 μm, and tissue adhesion strength of about 20−40 kPa. The hemolysis, cytotoxicity, and cellular double-staining assays indicate that those hydrogels had good biocompatibility and the H-3 hydrogel with higher glucose content gave a lower hemolysis ratio of 0.73%±0.14%. The blood-clotting index, blood cell attachment and adhesion studies showed those hydrogels had fast blood-coagulation, resulting in excellent hemostasis performance with a short hemostatic time of 38−46 s and less blood loss of 19%−34% in a liver hemorrhage model. A full-thickness rat-skin defect model further demonstrates that the H-3 hydrogel achieved fast wound healing with a wound closure of 70.0%±2.7% on postoperative day 7 and nearly full closure on day 14. Remarkably, the hydroproline level that denotes the collagen production reached a higher one of 7.24±0.55 μg/mg comparable to that in normal skins on day 14, evidencing the wound healing was close to completion in the H-3 treatment. Consequently, this work provides a simple method to construct a glycosylated and catechol-functionalized hydrogel platform from commercial EPL, holding translational potentials in wound hemostats and dressings.

Traditional cancer treatments have disadvantages of large trauma area and toxic side effects while killing cancer cells. Peptide-targeted sonodynamic therapy (SDT) can effectively improve specificity of cancer treatment and overcome the problem of low tissue penetration depth caused by a photo-driven therapy. Herein, we developed a porphyrin-based sonosensitizer with a water-soluble polymer as a biological carrier and a cRGD peptide for tumor targeting, which constituted a nano sonosensitizer (T-cRGD NPs) for fluorescence imaging-guided sonodynamic therapy. A comparable sonosensitizer (T-PEG NPs) without the targeting unit was also prepared for illustration of therapeutic performance. Attribute to the role of peptide targeting, T-cRGD NPs can accumulate and enter tumor cells for fluorescence imaging and show a superior SDT effect than T-PEG NPs in vitro. The imaging in vivo reveals that T-cRGD NPs can enrich in tumor tissues within 14 h with a good biocompatibility.