Injectable Supramolecular Hydrogels for In Situ Programming of Car-T Cells toward Solid Tumor Immunotherapy.

Chimeric antigen receptor (CAR)-T cell immunotherapy is approved in the treatment of hematological malignancies, but remains far from satisfactory in solid tumor treatment due to inadequate intra-tumor CAR-T cell infiltration. Herein, an injectable supramolecular hydrogel system, based on self-assembly between cationic polymer mPEG-PCL-PEI (PPP) conjugated with T cell targeting anti-CD3e f(ab')2 fragment and α-cyclodextrin (α-CD), is designed to load plasmid CAR (pCAR) with a T cell specific CD2 promoter, which successfully achieves in situ fabrication and effective accumulation of CAR-T cells at the tumor site in humanized mice models. More importantly, due to this tumor microenvironment reprogramming, secretion of cellular inflammatory cytokines (interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ)) or tumor killer protein granzyme B is significantly promoted, which reverses the immunosuppressive microenvironment and significantly enhances the intra-tumor CAR-T cells and cytotoxic T cells infiltration. To the best of the current knowledge, this is a pioneer report of using injectable supramolecular hydrogel for in situ reprogramming CAR-T cells, which might be beneficial for solid tumor CAR-T immunotherapy.

Topsoil selenium (Se) under Se-rich farming in China: Current status, cropping impacts and ecological risk assessment.

Selenium (Se), as an essential microelement, can be supplied through Se-biofortified food from Se-rich soils and associated farming practices for human health, while it can also cause eco-risks if overapplied. In this study, a multi-scale spatiotemporal meta-analysis was conducted to guide sustainable Se-rich farming in China by combining a long-term survey with a reviewed database. The weighted mean concentration, spatial distribution of soil Se, nationwide topsoil Se variation from cropping impacts and its bioavailability-based ecological risks were assessed and quantified. The results showed that the weighted mean content (0.3 mg kg-1) of China was slightly higher than that of previous nationwide topsoil Se surveys, as more Se-rich areas were found in recent high-density sampling surveys. Cropping has overall reduced Se content by 9.5% from farmland across China and deprived more with the increase in farming rotation driven by geo-climatic conditions. Long-term cropping removed Se from Se-rich areas but accumulated it in Se-deficient areas. Additionally, the bioavailable Se content of topsoil in China ranged from 0 to 332 µg kg-1, and the bioavailability-based eco-risks indicated that high eco-risks only existed in overfertilized and extremely high-Se soils, such as in Enshi, Ziyang and some coalfield areas. This work provides evidence for the development of sustainable Se-rich farming with proper utilization of soil Se resources, simultaneously protecting the soil eco-environment.

Ciprofloxacin enhances cadmium toxicity to earthworm Eisenia fetida by altering the gut microorganism composition.

The concurrent existence of cadmium (Cd) and ciprofloxacin (CIP) in agricultural soils is very common, but presents a challenge to soil organisms. As more attention has been paid to the effect of toxic metals on the migration of antibiotic resistance genes, the critical role of the gut microbiota in CIP-modifying Cd toxicity in earthworms remains unclear. In this study, Eisenia fetida was exposed to Cd and CIP alone or in combination at environmentally relevant concentrations. Cd and CIP accumulation in earthworm increased as their respective spiked concentrations increased. In fact, Cd accumulation increased by 39.7% when 1 mg/kg CIP was added; however, the addition of Cd did not affect CIP uptake. Compared with exposure to Cd alone, a greater ingestion of Cd following combined exposure to Cd and 1 mg/kg CIP resulted in greater oxidative stress and energy metabolism disturbances in earthworms. The reactive oxygen species (ROS) contents and apoptosis rate of coelomocytes were more sensitive to Cd than these biochemical indicators. In fact, 1 mg/kg Cd induced the derivation of ROS. Similarly, the toxicity of Cd (5 mg/kg) to coelomocytes was promoted by CIP (1 mg/kg), ROS content in coelomocytes and the apoptosis rate increased by 29.2% and 113.1%, respectively, due to increased Cd accumulation. Further investigation of the gut microorganisms revealed that the decreased abundance of Streptomyces strains (known as Cd accumulation taxa) could be a critical factor for enhanced Cd accumulation and greater Cd toxicity to earthworms following exposure to both Cd and CIP; this was because this microorganism group was eliminated by the simultaneous ingestion of CIP. This study stressed the role of gut microorganisms in altering the toxicity of Cd and CIP combined contamination in soil organisms. More attention should be paid to the ecological risks of such combined contamination in soils.

Cholesterol-stabilized membrane-active nanopores with anticancer activities.

Cholesterol-enhanced pore formation is one evolutionary means cholesterol-free bacterial cells utilize to specifically target cholesterol-rich eukaryotic cells, thus escaping the toxicity these membrane-lytic pores might have brought onto themselves. Here, we present a class of artificial cholesterol-dependent nanopores, manifesting nanopore formation sensitivity, up-regulated by cholesterol of up to 50 mol% (relative to the lipid molecules). The high modularity in the amphiphilic molecular backbone enables a facile tuning of pore size and consequently channel activity. Possessing a nano-sized cavity of ~ 1.6 nm in diameter, our most active channel Ch-C1 can transport nanometer-sized molecules as large as 5(6)-carboxyfluorescein and display potent anticancer activity (IC50 = 3.8 µM) toward human hepatocellular carcinomas, with high selectivity index values of 12.5 and >130 against normal human liver and kidney cells, respectively.

Dual Tumor Microenvironment Remodeling by Glucose-Contained Radical Copolymer for MRI-Guided Photoimmunotherapy.

Aberrant glucose metabolism and immune evasion are recognized as two hallmarks of cancer, which contribute to poor treatment efficiency and tumor progression. Herein, a novel material system consisting of a glucose and TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl) at the distal ends of PEO-b-PLLA block copolymer (glucose-PEO-b-PLLA-TEMPO), is designed to encapsulate clinical therapeutics CUDC101 and photosensitizer IR780. The specific core-shell rod structure formed by the designed copolymer renders TEMPO radicals excellent stability against reduction-induced magnetic resonance imaging (MRI) silence. Tumor-targeting moiety endowed by glucose provides the radical copolymer outstanding multimodal imaging capabilities, including MRI, photoacoustic imaging, and fluorescence imaging. Efficient delivery of CUDC101 and IR780 is achieved to synergize the antitumor immune activation through IR780-mediated photodynamic therapy (PDT) and CUDC101-triggered CD47 inhibition, showing M1 phenotype polarization of tumor-associated macrophages (TAMs). More intriguingly, this study demonstrates PDT-stimulated p53 can also re-educate TAMs, providing a combined strategy of using dual tumor microenvironment remodeling to achieve the synergistic effect in the transition from cold immunosuppressive to hot immunoresponsive tumor microenvironment.

Emerging Biomaterials-Based Strategies for Inhibiting Vasculature Function in Cancer Therapy.

The constant feeding of oxygen and nutrients through the blood vasculature has a vital role in maintaining tumor growth. Interestingly, recent endeavors have shown that nanotherapeutics with the strategy to block tumor blood vessels feeding nutrients and oxygen for starvation therapy can be helpful in cancer treatment. However, this field has not been detailed. Hence, this review will present an exhaustive summary of the existing biomaterial based strategies to disrupt tumor vascular function for effective cancer treatment, including hydrogel or nanogel-mediated local arterial embolism, thrombosis activator loaded nano-material-mediated vascular occlusion and anti-vascular drugs that block tumor vascular function, which may be beneficial to the design of anti-cancer nanomedicine by targeting the tumor vascular system.

Directional Transportation in a Self-Pumping Dressing Based on a Melt Electrospinning Hydrophobic Mesh.

Self-pumping wound dressings with directional water transport ability have been widely studied for their function of directional extraction of excessive biofluid from wounds while keeping the wound in a moderately humid environment to realize rapid wound healing. However, the existing solutions have not paid close attention to the fabrication of a nonirritating hydrophobic layer facing the wounds, which may cause irritation to wounds and thereby further worsen inflammation. Herein, a flexible and elastic thermoplastic polyurethane (TPU) hydrophobic microfiber mesh (TPU-HMM) produced by melt electrospinning (MES) is reported. The TPU-HMM was compounded to a hydrophilic nanofiber membrane, which was fabricated by blending with polyamide 6 and poly(ethylene glycol) (PA6-PEG) to form a composite self-pumping dressing, for which the breakthrough pressure in a reverse direction was 12.8 times than that in a positive direction and the forward water transmission rate was increased by 700%. It shows good directional water transport ability and is expected to absorb excessive biofluid of the wounds. This solvent-free and easy-process TPU-HMM provides a new strategy for the development of functional self-pumping textiles, and the solvent-free fabrication method for fibers, which eliminates the potential toxicity brought by solvent residues, offers more possibilities for its applications in biomedicine.

Convenient Tuning of the Elasticity of Self-Assembled Nano-Sized Triterpenoids to Regulate Their Biological Activities.

The impact of the mechanical properties of nanomedicines on their biological functions remains elusive due to the difficulty in tuning the elasticity of the vehicles without changing chemistry. Herein, we report the fabrication of elasticity-tunable self-assembled oleanolic acid (OA) nanoconstructs in an antiparallel zigzag manner and develop rigid nanoparticles (OA-NP) and flexible nanogels (OA-NG) as model systems to decipher the elasticity-biofunction relationship. OA-NG demonstrate less endocytosis and enhanced lysosome escape with deformation compared to OA-NP. Further in vitro and in vivo experiments show the active permeation of OA-NG into the interior of tumor with enhanced antitumor efficacy accompanied by decreased collagen production and eight- to tenfold immune cell infiltration. This study not only presents a facile and green strategy to develop flexible OA-NG for effective cancer treatment but also uncovers the crucial role of elasticity in regulating biological activity, which may provide reference for precise design of efficient nanomedicines.

Enhanced drug retention by anthracene crosslinked nanocomposites for bimodal imaging-guided phototherapy.

Efficient drug delivery, multifunctional combined therapy and real-time diagnosis are the main hallmarks in the exploitation of precision nanomedicine. Herein, an anthracene-functionalized micelle containing a magnetic resonance imaging (MRI) contrast agent, upconversion nanoparticles (UCNPs) and the photosensitizer IR780 is designed to achieve sustained drug release and enhanced photothermal and photodynamic therapy. The polymer-coated hybrid micelle was achieved by crosslinking anthracene-dimer with UV light (λ > 300 nm), which is converted from near-infrared (NIR) irradiation upon UCNPs. Besides, the water-insoluble photosensitizer IR780 is introduced into the system to achieve efficient drug delivery and photothermal and photodynamic synergistic therapy. As a consequence of NIR-induced anthracene-dimer formation, the cross-linked nanocomposite shows sustained drug release, and the enhanced retention effect of IR780 could increase the photothermal conversion efficiency. Importantly, the incorporation of 2,2,6,6-tetramethyl-piperidineoxyl (TEMPO) as a nitroxide MRI contrast agent presents the potential for real-time diagnosis via nanotheranostics, and the fluorescence imaging of IR780 is applied to monitor drug distribution and metabolism. This strategy of sustained drug delivery by anthracene-dimer formation through the better penetration depth of NIR-II fluorescence provides an executable platform to achieve enhanced phototherapy in biomedical applications.

Cyclodextrin-Based Hybrid Polymeric Complex to Overcome Dual Drug Resistance Mechanisms for Cancer Therapy.

Drug resistance always reduces the efficacy of chemotherapy, and the classical mechanisms of drug resistance include drug pump efflux and anti-apoptosis mediators-mediated non-pump resistance. In addition, the amphiphilic polymeric micelles with good biocompatibility and high stability have been proven to deliver the drug molecules inside the cavity into the cell membrane regardless of the efflux of the cell membrane pump. We designed a cyclodextrin (CD)-based polymeric complex to deliver chemotherapeutic doxorubicin (DOX) and Nur77ΔDBD gene for combating pumps and non-pump resistance simultaneously. The natural cavity structure of the polymeric complex, which was comprised with ß-cyclodextrin-graft-(poly(ε-caprolactone)-adamantly (ß-CD-PCL-AD) and ß-cyclodextrin-graft-(poly(ε-caprolactone)-poly(2-(dimethylamino) ethyl methacrylate) (ß-CD-PCL-PDMAEMA), can achieve the efficient drug loading and delivery to overcome pump drug resistance. The excellent Nur77ΔDBD gene delivery can reverse Bcl-2 from the tumor protector to killer for inhibiting non-pump resistance. The presence of terminal adamantyl (AD) could insert into the cavity of ß-CD-PCL-PDMAEMA via host-guest interaction, and the releasing rate of polymeric inclusion complex was higher than that of the individual ß-CD-PCL-PDMAEMA. The polymeric inclusion complex can efficiently deliver the Nur77ΔDBD gene than polyethylenimine (PEI-25k), which is a golden standard for nonviral vector gene delivery. The higher transfection efficacy, rapid DOX cellular uptake, and significant synergetic tumor cell viability inhibition were achieved in a pump and non-pump drug resistance cell model. The combined strategy with dual drug resistance mechanisms holds great potential to combat drug-resistant cancer.

Flexible polymeric nanosized micelles for ophthalmic drug delivery: research progress in the last three years.

The eye is a complex structure with a variety of anatomical barriers and clearance mechanisms, so the provision of safe and effective ophthalmic drug delivery technology is a major challenge. In the past few decades, a number of reports have shown that nano-delivery platforms based on polymeric micelles are of great interest, because of their hydrophobic core that encapsulates lipid-soluble drugs and small size with high penetration, allowing long-term drug retention and posterior penetration in the eye. Furthermore, as an ocular delivery platform, polymeric micelles not only cover the single micellar drug delivery system formed by poloxamer, chitosan or other polymers, but also include composite drug delivery systems like micelle-encapsulated hydrogels and micelle-embedded contact lenses. In this review, a number of ophthalmic micelles that have emerged in the last three years will be systematically reviewed, with a summary of and discussion on their unique advantages or unique drug delivery performance. Last but not least, the current challenges of polymeric micelle formulations in potential clinical ophthalmic therapeutic applications will also be proposed, which might be helpful for future design of ocular drug delivery formulations.

Thermosensitive Poly(DHSe/PEG/PPG Urethane)-Based Hydrogel Extended Remdesivir Application in Ophthalmic Medication.

The spread of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) outbreak beginning in March 2020. Currently, there is a lack of suitable dose formulations that interrupt novel coronavirus transmission via corneal and conjunctival routes. In the present study, we developed and evaluated a thermosensitive gelling system based on a selenium-containing polymer for topical ocular continuous drug release. In detail, di-(1-hydroxylundecyl) selenide (DHSe), poly(ethylene glycol) (PEG), and poly(propylene glycol) (PPG) were polymerized to form poly(DHSe/PEG/PPG urethane). The polymer was used to carry poorly water-soluble remdesivir (RDV) at room temperature to form the final thermosensitive in situ gel, which exhibited a typical sol-gel transition at 35 °C. The formed polymer was further characterized by rheology, thermology, and scanning electron microscopy. In vitro release studies and in vivo retention and penetration tests indicated that the thermogel provided the prolonged release of RDV. The RDV-loaded in situ gel was proven to be non-biotoxic against human corneal epithelial cells, with good ocular tolerance and biocompatibility in rabbit eyes.

Enhanced Healing and Antimicrobial Efficacy of Chitosan-g-Polyacrylamide in a Rat Model of Gingival Ulcers.

Patients in dental hospitals often experience oral ulcerative lesions, which lead to pain and affect the patient's quality of life. At present, the goal of treating oral ulcerative lesions with drugs is to reduce inflammation and promote ulcer healing. However, very few antibacterial and hemostatic drugs are designed to be suitable for the microenvironment of gingival ulcers. Based on this, we have designed a natural therapeutic agent for oral ulcerative lesions that meets the various requirements of oral ulcerative lesion medication. The chitosan-g-polyacrylamide (CP) copolymer is composed of chitosan as the main chain and polyacrylamide polymers as the side chains. Antibacterial experiments show that this polymer can effectively inhibit the proliferation of Gram-negative (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus). In vitro cell experiments also show that the CP copolymer is non-toxic, which is conducive to ulcer wound healing. Coagulation experiments prove that the CP copolymer can accelerate blood coagulation to stop bleeding. In experiments using a Wistar rat gingival ulcer model, the CP copolymer significantly promoted ulcer healing and shortened the healing time. These results indicate that the CP copolymer may serve as a potential therapeutic agent for oral ulcerative lesions.

Enhanced catalytic ozonation towards oxalic acid degradation over novel copper doped manganese oxide octahedral molecular sieves nanorods.

A series of copper doped manganese oxide octahedral molecular sieves (Cu-OMSx-T) with different Cu/Mn ratios and hydrothermal temperatures were successfully synthesized and used for catalytic ozonation towards oxalic acid (OA) degradation. The as-prepared Cu-OMSx-T composites were comprehensively investigated by BET, FT-IR, XPS and etc. characterizations. The results indicated that the Cu doping would increase the specific surface area, change chemical bonds, and promote the transformation of multivalent metals and the generation of oxygen vacancies. It was noteworthy that the hydrothermal temperature played an important role in the morphology of Cu-OMSx-T composites and the Cu/Mn molar ratios greatly influenced the catalytic activities. Amongst, the Cu-OMS0.5-140 achieved the optimum catalytic activity with 97.3% of OA degradation efficiency and 98.8% of mineralization rate in 30 min at pH 6.0. Moreover, hydroxyl radical and superoxide radical were identified as the major reactive radicals and the catalytic mechanism for OA degradation enhancement was also elucidated. In addition, the Cu-OMS0.5-140 exhibited great stability and reusability with high OA mineralization rate (>90%) and low metal release after five times recycle. Overall, the results indicated that the synthesized Cu-OMS0.5-140 is an efficient, stable, and recyclable ozonation catalyst, and could be a promising alternative material for water purification.