Immunoregulation in Skull Defect Repair with a Smart Hydrogel Loaded with Mesoporous Bioactive Glasses.

Skull defect repair is a complex and critical medical challenge, and there is an urgent need to develop multifunctional tissue engineering scaffolds for skull regeneration. The success of bone tissue engineering depends on the construction of scaffolds that can regulate the immune microenvironment of bone regeneration and mimic the liquid crystal and viscoelastic properties of natural bone extracellular matrix. Hence, a smart hydrogel (PEGDA5/AM15/CLC-BMP-4@MBG) with good biocompatibility and the ability to modulate the wound immune microenvironment has been developed for the repair of skull defects. The hydrogel consists of chitin liquid crystal hydrogel (PEGDA5/AM15/CLC) and mesoporous bioactive glasses (MBGs) loaded with bone morphogenetic protein-4 (BMP-4). The liquid crystal hydrogel not only offers the necessary biological support and mechanical properties but also maintains the stability of the liquid crystal state, facilitating adhesion and regeneration of surrounding bone tissue. In addition, BMP-4@MBG intelligently regulates the release rate of BMP-4 in response to changes in wound microenvironment, thus effectively promoting the transformation of macrophages from M1 to M2 macrophages. At the same time, Ca2+ and Si4+ released by MBG degradation and BMP-4 synergically promote bone repair process. The PEGDA5/AM15/CLC-BMP-4@MBG hydrogel shows excellent immunomodulatory and osteogenic properties of bone microenvironment and is a promising scaffold material for bone tissue engineering.

A novel doxorubicin/CTLA-4 blocker co-loaded drug delivery system improves efficacy and safety in antitumor therapy.

Doxorubicin's antitumor effectiveness may be constrained with ineffective tumor penetration, systemic adverse effects, as well as drug resistance. The co-loading of immune checkpoint inhibitors and doxorubicin into liposomes can produce synergistic benefits and address problems, including quick drug clearance, toxicity, and low drug penetration efficiency. In our previous study, we modified a nanobody targeting CTLA-4 onto liposomes (LPS-Nb36) to be an extremely potent CTLA-4 signal blocker which improve the CD8+ T-cell activity against tumors under physiological conditions. In this study, we designed a drug delivery system (LPS-RGD-Nb36-DOX) based on LPS-Nb36 that realized the doxorubicin and anti-CTLA-4 Nb co-loaded and RGD modification, and was applied to antitumor therapy. We tested whether LPS-RGD-Nb36-DOX could targets the tumor by in vivo animal photography, and more importantly, promote cytotoxic T cells proliferation, pro-inflammatory cytokine production, and cytotoxicity. Our findings demonstrated that the combination of activated CD8+ T cells with doxorubicin/anti-CTLA-4 Nb co-loaded liposomes can effectively eradicate tumor cells both in vivo and in vitro. This combination therapy is anticipated to have synergistic antitumor effects. More importantly, it has the potential to reduce the dose of chemotherapeutic drugs and improve safety.

PD-1 blocking strategy for enhancing the anti-tumor effect of CAR T cells targeted CD105.

Purpos: CD105 has become a promising target of immunotherapy development for highly specific expression on the neovascular surface of most types of tumor cells. In previous studies, we constructed a CAR T cell (CD105 CAR T cell) and observed significant antitumor activity. In this study, we optimized the structure of CD105 CAR to increase PD-1 antibody secretion function (CD105 × PD-1 CAR T cells). Methods: we tested whether Increased PD-1 antibody secretion with CAR T cells targeted CD105 could promote in vitro proliferation, proinflammatory cytokine production and cytotoxicity,or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy. Results: Our data showed that the PD-1 antibody secreted by CD105 × PD-1 CAR T cells could specifically bind to the PD-1 receptor of T cells then blocked the PD-1/PD-L-1 signaling pathway, thus enhancing the activation and proliferation of CAR T cells. After incubation of CD105 × PD-1 CAR T cells with HepG2 as a hepatocellular carcinoma cell line expressing CD105, the results showed that CD105 × PD-1 CAR T cells increased the expression levels of CD69 and CD62L, enhanced the proliferation capacity of CAR T cells, and secreted more IL-2, TNF-α and IFN-γ than CD105 CAR T cells. Conclusion: These data showed that CD105 × PD-1 CAR T cells was specifically killing tumor cells in vitro and in vivo. Our findings may therefore provide a promising new strategy for the improvement of CAR T therapy for solid tumors.

A novel CTLA-4 blocking strategy based on nanobody enhances the activity of dendritic cell vaccine-stimulated antitumor cytotoxic T lymphocytes.

Despite the great success of CTLA-4 blocking in cancer treatment, the use of anti-CTLA-4 monoclonal antibodies still faces many limitations. Now, immune checkpoint blocking coupled with adoptive cell therapy is gaining much attention. In this paper, we reported a strategy on the basis of anti-CTLA-4 nanobody (Nb)-modified liposomes to improve these obstacles. An Nb36/liposome complex was constructed and utilized as a blocker of the CTLA-4/B7 signal pathway in a combination with dendritic cell (DC)/tumor fusion vaccine to enhance the CD8+ T cell cytokine secretion, activation, proliferation, as well as specific cytotoxicity. Moreover, the CD8+ T cells induced by LPS-Nb36 and DC/tumor fusion vaccine led to higher CD8+ T cell effector function in vivo, which significantly retarded tumor growth and lengthened survival of tumor-bearing mice (HepG2, A549, and MGC-803). Our data demonstrate that the anti-CTLA-4 Nb-modified liposomes in connection with DC/tumor fusion vaccines enhance the CD8+ T cell antitumor activity in vitro and in vivo, and is expected to be an alternative therapy for patients with malignancies that have T cell dysfunction or have poor treatment against anti-CTLA-4 mAb.