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.

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 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.

Constructing nanocomplexes by multicomponent self-assembly for curing orthotopic glioblastoma with synergistic chemo-photothermal therapy.

The blood-brain barrier (BBB) is one of the major limitations of glioblastoma therapy in the clinic. Nanodrugs have shown great potential for glioblastoma therapy. Herein, we purposefully developed a multicomponent self-assembly nanocomplex with very high drug loading content for curing orthotopic glioblastoma with synergistic chemo-photothermal therapy. The nanocomplex consisted of self-assembled pH-responsive nanodrugs derived from amino acid-conjugated camptothecin (CPT) and canine dyes (IR783) coated with peptide Angiopep-2-conjugated copolymer of Ang-PEG-g-PLL. Specifically, the carrier-free nanocomplex exhibited a high drug loading content (up to 62%), good biocompatibility, and effective glioma accumulation ability. Moreover, the nanocomplex displayed good stability and pH-responsive behavior ex vivo. Both in vitro and in vivo results revealed that the nanocomplex could effectively cross the BBB and target glioma cells. Furthermore, the combination of chemotherapy and photothermal therapy of the nanocomplex achieved a better therapeutic effect, longer survival time, and minimized toxic side effects in orthotopic glioblastoma tumor-bearing nude mice. Overall, we modified the chemotherapeutic drug CPT so that it could self-assemble with other molecules into nanoparticles, which providing an alternative for the preparation of the carrier-free nanodrugs. The results highlighted the potential of self-assembly nanodrugs as a novel platform for effective glioblastoma therapy.