Glutathione-Responsive and Hydrogen Sulfide Self-Generating Nanocages Based on Self-Weaving Technology To Optimize Cancer Immunotherapy.

As an ideal drug carrier, it should possess high drug loading and encapsulation efficiency and precise drug targeting release. Herein, we utilized a template-guided self-weaving technology of phase-separated silk fibroin (SF) in reverse microemulsion (RME) to fabricate a kind of hyaluronic acid (HA) coated SF nanocage (HA-gNCs) for drug delivery of cancer immunotherapy. Due to the hollow structure, HA-gNCs were capable of simultaneous encapsulation of the anti-inflammatory drug betamethasone phosphate (BetP) and the immune checkpoint blockade (ICB) agent PD-L1 antibody (αPD-L1) efficiently. Another point worth noting was that the thiocarbonate cross-linkers used to strengthen the SF shell of HA-gNCs could be quickly broken by overexpressed glutathione (GSH) to reach responsive drug release inside tumor tissues accompanied by hydrogen sulfide (H2S) production in one step. The synergistic effect of released BetP and generated H2S guaranteed chronological modulation of the immunosuppressive tumor microenvironment (ITME) to amplify the therapeutic effect of αPD-L1 for the growth, metastasis, and recurrence of tumors. This study highlighted the exceptional prospect of HA-gNCs as a self-assistance platform for cancer drug delivery.

Regulation of rheumatoid arthritis microenvironment via a self-healing injectable hydrogel for improved inflammation elimination and bone repair.

The rheumatoid arthritis (RA) microenvironment is often followed by a vicious circle of high inflammation, endogenous gas levels imbalance, and poor treatment. To break the circle, we develop a dual-gas-mediated injectable hydrogel for modulating the immune microenvironment of RA and simultaneously releasing therapeutic drugs. The hydrogel (DNRS gel) could be broken down on-demand by consuming excessive nitric oxide (NO) and releasing therapeutic hydrogen sulfide (H2S), resulting in endogenous gas restoration, inflammation alleviation, and macrophage polarization to M2 type. Additionally, the hydrogel could suppress osteoclastogenesis and enhance osteogenesis. Furthermore, the intra-articularly injected hydrogel with methotrexate (MTX/DNRS gel) significantly alleviated inflammation and clinical symptoms and promoted the repair of bone erosion in the collagen-induced arthritis rat model. As a result, in vivo results demonstrated that MTX/DNRS gel restored the microenvironment and improved the therapeutic effect of MTX. This study provides a novel understanding of developing versatile smart delivery platforms for RA treatment.

A Versatile Chitosan-Based Hydrogel Accelerates Infected Wound Healing via Bacterial Elimination, Antioxidation, Immunoregulation, and Angiogenesis.

Drug-resistant bacterial infection of cutaneous wounds causes great harm to the human body. These infections are characterized by a microenvironment with recalcitrant bacterial infections, persistent oxidative stress, imbalance of immune regulation, and suboptimal angiogenesis. Treatment strategies available to date are incapable of handling the healing dynamics of infected wounds. A Schiff base and borate ester cross-linked hydrogel, based on phenylboronic acid-grafted chitosan (CS-PBA), dibenzaldehyde-grafted poly(ethylene glycol), and tannic acid (TA), is fabricated in the present study. Customized phenylboronic acid-modified zinc oxide nanoparticles (ZnO) are embedded in the hydrogel prior to gelation. The CPP@ZnO-P-TA hydrogel effectively eliminates methicillin-resistant Staphylococcus aureus (MRSA) due to the pH-responsive release of Zn2+ and TA. Killing is achieved via membrane damage, adenosine triphosphate reduction, leakage of intracellular components, and hydrolysis of bacterial o-nitrophenyl-ß-d-galactopyranoside. The CPP@ZnO-P-TA hydrogel is capable of scavenging reactive oxygen and nitrogen species, alleviating oxidative stress, and stimulating M2 polarization of macrophages. The released Zn2+ and TA also induce neovascularization via the PI3K/Akt pathway. The CPP@ZnO-P-TA hydrogel improves tissue regeneration in vivo by alleviating inflammatory responses, stimulating angiogenesis, and facilitating collagen deposition. These findings suggest that this versatile hydrogel possesses therapeutic potential for the treatment of MRSA-infected cutaneous wounds.

Non-Pore Dependent and MMP-9 Responsive Gelatin/Silk Fibroin Composite Microparticles as Universal Delivery Platform for Inhaled Treatment of Lung Cancer.

Developing a drug delivery platform that possesses universal drug loading capacity to meet various requirements of cancer treatment is a challenging yet interesting task. Herein, a self-assembled gelatin/silk fibroin composite (GSC) particle based drug delivery system is developed via microphase separation followed by desolvation process. Thanks to its preassembled microphase stage, this GSC system is suitable for varying types of drugs. The desolvation process fix drugs inside GSC rapidly and densify the GSC structure, thereby achieving efficient drug loading and providing comprehensive protection for loaded drugs. Actually, the size of this brand-new non-pore dependent drug delivery system can be easily adjusted from 100 nm to 20 µm to fit different scenarios. This work selects GSC with 3 µm diameter as the universal inhaled drug delivery platform, which shows an excellent transmucosal penetration and lung retention ability. Additionally, the MMP-9 sensitive degradation property of GSC enhances the targeted efficiency of drugs and reduces side effects. Intestinally, GSC can self-amplify the regulation of innate immunity to reverse the cancerous microenvironment into an antitumor niche, significantly improving the therapeutic effect of drugs. This study of GSC universal drug platform provides a new direction to develop the next-generation of drug delivery system for lung cancer.

Regulation of localized corrosion of 316L stainless steel on osteogenic differentiation of bone morrow derived mesenchymal stem cells.

Localized corrosion has become a concerning issue in orthopedic implants as it is associated with peri-implant adverse tissue reactions and implant failure. Here, the pitting corrosion of 316 L stainless steels (316 L SSs) was initiated by electrochemical polarization to simulate the in vivo localized corrosion of orthopedic implants. The effect of localized corrosion on osteogenic differentiation of bone marrow derived mesenchymal stem cells (BMSCs) was systematically studied. The results suggest that pitting corrosion of 316 L SS reduced the viability, adhesion, proliferation, and osteogenic differentiation abilities of BMSCs, especially for the cells around the corrosion pits. The relatively high concentrations of metallic ions such as Cr3+ and Ni2+ released by pitting corrosion could cause cytotoxicity to the BMSCs. The inhomogeneous electrochemical environment resulted from localized corrosion could promote reactive oxygen species (ROS) generation around the corrosion pits and cause oxidative stress of BMSCs. In addition, localized corrosion could also electrochemically interact with the cells and lead to cell membrane depolarization. The depolarized cell membranes and relatively high levels of ROS mediated the degradation of the osteogenic capacity of BMSCs. This work provides new insights into corrosion-mediated cell function degeneration as well as the material-cell interactions.

Enhanced Immunogenic Cell Death and Antigen Presentation via Engineered Bifidobacterium bifidum to Boost Chemo-immunotherapy.

The immunogenic cell death (ICD) of tumor cells has aroused great interest in the field of immunotherapy, mainly due to the production of plentiful tumor-associated antigens (TAAs) and damage-associated molecule patterns. However, doxorubicin (DOX)-induced tumor-specific T-cell-mediated immune response is usually very weak because of antigen presentation deficiency and the immunosuppressive tumor microenvironment (ITME). Herein, the probiotic Bifidobacterium bifidum (Bi) was covalently modified with DOX-loaded CaP/SiO2 nanoparticles (DNPs@Bi) for tumor therapy. On one hand, the pH-responsive release of DOX could induce chemotherapy and ICD in the ITME. On the other hand, tumor-targeting Bi is able to significantly enhance the presentation of TAAs from B16F10 cells to DCs via Cx43-dependent gap junctions. Due to the combination of enhanced ICD and TAAs presentation, the maturation of DCs and the infiltration of cytotoxic T lymphocytes in the ITME were stimulated. As a result, in vivo antitumor experiments demonstrated that DNPs@Bi prolonged the survival rate and significantly inhibited the tumor progression and metastasis. This strategy of bacterial-driven hypoxia-targeting delivery systems offers a promising approach to tumor chemo-immunotherapy.

Nitric Oxide Scavenging and Hydrogen Sulfide Production Synergistically Treat Rheumatoid Arthritis.

To restore the disordered endogenous gas levels is an efficient alternative for the treatment of rheumatoid arthritis (RA). Both insufficient hydrogen sulfide (H2 S) and excessive nitric oxide (NO) contribute to synovial inflammation. Herein, a new block polymer PEG10 -b-PNAPA30 -b-PEG10 composed of an NO-responsive monomer and a cysteine-triggered H2 S donor, which can simultaneously scavenge NO and release therapeutic H2 S for RA treatment, is reported. In vitro experiments demonstrate that the polymer exhibits a synergistic effect on suppressing reactive oxygen species levels and pro-inflammatory cytokine production via NF-κB signaling pathway. It leads to the polarization of macrophages from M1 to M2 phenotype. Moreover, the released H2 S further restrains NO production by suppressing the expression of iNOS. In vivo experiments with an RA rat model show that the system markedly mitigates the synovial inflammation, osteoporosis, and clinical symptoms of RA rats, which is attributed to the combination therapy of H2 S release and NO depletion. This work provides new insight into the synergistic treatment of RA and endogenous gas-related diseases.

Construction of Wogonin Nanoparticle-Containing Strontium-Doped Nanoporous Structure on Titanium Surface to Promote Osteoporosis Fracture Repair.

M2 polarization of macrophage is an important immunomodulatory event that attenuates inflammation. To regulate the immune microenvironment in osteoporotic conditions for enhancing bone healing, strontium-doped nano-structure is fabricated on the surface of titanium implant via microarc oxidation and electrochemical deposition technology, followed by the addition of multiplayer coatings embedded with silk fibroin-based wogonin nanoparticles (Ti-MAO/Sr/LBLWNP ) by layer-by-layer self-assembly technique (LBL). It is found that Ti-MAO/Sr/LBLWNP can release wogonin and Sr2+ in a sustainable manner for more than 7 and 21 days. In vitro studies show that Ti-MAO/Sr/LBLWNP significantly upregulates the expression of CD206 while reducing the expression of CD86. Meanwhile, Ti-MAO/Sr/LBLWNP can promote the expression level of M2 macrophage anti-inflammatory factor (TGF-ß1, Arg-1), which improves the proliferation and osteogenic differentiation of osteoblasts through paracrine signaling. Compared to bare titanium, Ti-MAO/Sr/LBLWNP significantly inhibits the expression of inflammatory factors around the implant and effectively promotes new bone formation at pre-implant interface after implantation for 4 weeks. This study provides a simple and effective method to develop functional titanium alloy materials for osteoporotic fracture repair.

Multienzyme-like Reactivity Cooperatively Impairs Glutathione Peroxidase 4 and Ferroptosis Suppressor Protein 1 Pathways in Triple-Negative Breast Cancer for Sensitized Ferroptosis Therapy.

Ferroptosis is a recently discovered route of regulated cell death that offers the opportunities for the treatment of chemotherapy-resistant tumor indications, but its efficacy can be affected by the glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) antioxidant mechanisms, posing significant challenges for its clinical translation. In this study, we report a Cu-tetra(4-carboxyphenyl)porphyrin chloride(Fe(III)) (Cu-TCPP(Fe)) metal organic framework (MOF)-based nanosystem for the efficient incorporation of Au nanoparticles (NPs) and RSL3, which can demonstrate enzyme-like activities to universally suppress the antiferroptotic pathways in tumor cells for amplifying ferroptotic damage. Herein, Cu-TCPP(Fe) MOF nanosheets were integrated with Au NPs via in situ nucleation and loaded with RSL3 via π-π stacking, which were eventually modified with polyethylene glycol (PEG) and iRGD for tumor-targeted drug delivery. Specifically, the Au NPs can demonstrate glucose oxidase-like activities for efficient glucose depletion, thus disrupting the pentose phosphate pathway to impede reduced glutathione (GSH) biosynthesis and prevent the recycling of coenzyme Q10 (CoQ10) to CoQ10H2, while Cu species can oxidize GSH into oxidized glutathione (GSSG). These nanocatalytic activities can lead to the simultaneous inhibition of the GPX4/GSH and FSP1/CoQ10H2 pathways and cooperate with the GPX4-deactivating function of RSL3 to cause pronounced ferroptotic damage, thereby providing a strong rationale for the application of ferroptosis therapy in the clinic.

A Machine Learning Driven Pipeline for Automated Photoplethysmogram Signal Artifact Detection.

Recent advances in Critical Congenital Heart Disease (CCHD) research using Photoplethysmography (PPG) signals have yielded an Internet of Things (IoT) based enhanced screening method that performs CCHD detection comparable to SpO2 screening. The use of PPG signals, however, poses a challenge due to its measurements being prone to artifacts. To comprehensively study the most effective way to remove the artifact segments from PPG waveforms, we performed feature engineering and investigated both Machine Learning (ML) and rule based algorithms to identify the optimal method of artifact detection. Our proposed artifact detection system utilizes a 3-stage ML model that incorporates both Gradient Boosting (GB) and Random Forest (RF). The proposed system achieved 84.01% of Intersection over Union (IoU), which is competitive to state-of-the-art artifact detection methods tested on higher resolution PPG.