Lymph node-biomimetic scaffold boosts CAR-T therapy against solid tumor.

The limited infiltration and persistence of chimeric antigen receptor (CAR)-T cells is primarily responsible for their treatment deficits in solid tumors. Here, we present a three-dimensional scaffold, inspired by the physiological process of T-cell proliferation in lymph nodes. This scaffold gathers the function of loading, delivery, activation and expansion for CAR-T cells to enhance their therapeutic effects on solid tumors. This porous device is made from poly(lactic-co-glycolic acid) by a microfluidic technique with the modification of T-cell stimulatory signals, including anti-CD3, anti-CD28 antibodies, as well as cytokines. This scaffold fosters a 50-fold CAR-T cell expansion in vitro and a 15-fold cell expansion in vivo. Particularly, it maintains long-lasting expansion of CAR-T cells for up to 30 days in a cervical tumor model and significantly inhibits the tumor growth. This biomimetic delivery strategy provides a versatile platform of cell delivery and activation for CAR-T cells in treating solid tumors.

Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells.

Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.

Cryo-shocked tumor cells deliver CRISPR-Cas9 for lung cancer regression by synthetic lethality.

Although CRISPR-mediated genome editing holds promise for cancer therapy, inadequate tumor targeting and potential off-target side effects hamper its outcomes. In this study, we present a strategy using cryo-shocked lung tumor cells as a CRISPR-Cas9 delivery system for cyclin-dependent kinase 4 (CDK4) gene editing, which initiates synthetic lethal in KRAS-mutant non-small cell lung cancer (NSCLC). By rapidly liquid nitrogen shocking, we effectively eliminate the pathogenicity of tumor cells while preserving their structure and surface receptor activity. This delivery system enables the loaded CRISPR-Cas9 to efficiently target to lung through the capture in pulmonary capillaries and interactions with endothelial cells. In a NSCLC-bearing mouse model, the drug accumulation is increased nearly fourfold in lung, and intratumoral CDK4 expression is substantially down-regulated compared to CRISPR-Cas9 lipofectamine nanoparticles administration. Furthermore, CRISPR-Cas9 editing-mediated CDK4 ablation triggers synthetic lethal in KRAS-mutant NSCLC and prolongs the survival of mice.

Effects of hydroxy methionine zinc on growth performance, immune response, antioxidant capacity, and intestinal microbiota of red claw crayfish (Procambarus clarkii).

This study aimed to evaluate the effects of varying zinc (Zn) levels on the growth performance, non-specific immune response, antioxidant capacity, and intestinal microbiota of red claw crayfish (Procambarus clarkii (P. clarkii)). Adopting hydroxy methionine zinc (Zn-MHA) as the Zn source, 180 healthy crayfish with an initial body mass of 6.50 ± 0.05 g were randomly divided into the following five groups: X1 (control group) and groups X2, X3, X4, and X5, which were fed the basal feed supplemented with Zn-MHA with 0, 15, 30, 60, and 90 mg kg-1, respectively. The results indicated that following the addition of various concentrations of Zn-MHA to the diet, the following was observed: Specific growth rate (SGR), weight gain rate (WGR), total protein (TP), total cholesterol (TC), the activities of alkaline phosphatase (AKP), phenoloxidase (PO), total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD) and catalase (CAT), the expression of CTL, GPX, and CuZn-SOD genes demonstrated a trend of rising and then declining-with a maximum value in group X4-which was significantly higher than that in group X1 (P < 0.05). Zn deposition in the intestine and hepatopancreas, the activity of GSH-PX, and the expression of GSH-PX were increased, exhibiting the highest value in group X5. The malonaldehyde (MDA) content was significantly reduced, with the lowest value in group X4, and the MDA content of the Zn-MHA addition groups were significantly lower than the control group (P < 0.05). In the analysis of the intestinal microbiota of P. clarkii, the number of operational taxonomic units in group X4 was the highest, and the richness and diversity indexes of groups X3 and X4 were significantly higher than those in group X1 (P < 0.05). Meanwhile, the dietary addition of Zn-MHA decreased and increased the relative abundance of Proteobacteria and Tenericutes, respectively. These findings indicate that supplementation of dietary Zn-MHA at an optimum dose of 60 mg kg-1 may effectively improve growth performance, immune response, antioxidant capacity, and intestinal microbiota richness and species diversity in crayfish.

Engineered bacteria for augmented in situ tumor vaccination.

In situ tumor vaccination has aroused tremendous interest with its capability for eliciting strong and systemic antitumor immune responses. Unlike traditional cancer vaccines, in situ tumor vaccination avoids the laborious process of tumor antigen identification and can modulate tumor immunosuppressive microenvironment at the same time. In recent years, bacteria have been used as both efficient tumor-targeted delivery vehicles and potent adjuvants. Regarding the rapid development in this area, in this review, we summarize recent advances in the application of bacteria for in situ cancer vaccination. We illustrate the mechanisms of bacteria as both efficient tumor immunogenic cell death inducers and tumor-targeted delivery platforms. Then we comprehensively review the engineering strategies for designing bacteria-based in situ vaccination, including chemical modification, nanotechnology, and genetic engineering. The current dilemma and future directions are discussed at the end of this review.

Cell delivery devices for cancer immunotherapy.

Adoptive cell therapy (ACT) that leverages allogeneic or autologous immune cells holds vast promise in targeted cancer therapy. Despite the tremendous success of ACT in treating hematopoietic malignancies, its efficacy is limited in eradicating solid tumors via intravenous infusion of immune cells. With the extending technology of cancer immunotherapy, novel delivery strategies have been explored to improve the therapeutic potency of adoptively transferred cells for solid tumor treatment by innovating the administration route, maintaining the cell viability, and normalizing the tumor microenvironment. In this review, a variety of devices for cell delivery are summarized. Perspectives and challenges of cell delivery devices for cancer immunotherapy are also discussed.

Climatic Variability Caused by Topographic Barrier Prevents the Northward Spread of Invasive Ageratina adenophora.

Ageratina adenophora (Spreng.) R.M.King & H.Rob. is one of the most threatening invasive alien plants in China. Since its initial invasion into Yunnan in the 1940s, it spread rapidly northward to southern Mount Nyba in Sichuan, which lies on the eastern edge of the Qinghai-Tibet Plateau. During fieldwork, we found an interesting phenomenon: A. adenophora failed to expand northward across Mount Nyba, even after the opening of the 10 km tunnel, which could have served as a potential corridor for its spread. In this work, to explore the key factors influencing its distribution and spread patterns, we used a combination of ensemble species distribution models with the MigClim model. We found that the temperature annual range (TAR), precipitation of driest month (PDM), highway density (HW), and wind speed (WS) were the most predominant factors affecting its distribution. The north of Mount Nyba is not suitable for A. adenophora survival due to higher TAR. The spatial-temporal dynamic invasion simulation using MigClim further illustrated that the northward invasion of A. adenophora was stopped by Mount Nyba. Overall, Mount Nyba may act as a topographic barrier that causes environmental differences between its south and north sides, preventing the northward invasion of A. adenophora. However, other suitable habitats on the northern side of the mountain still face challenges because A. adenophora is likely to invade via other routes. Therefore, long-term monitoring is needed to prevent human-induced long-distance spread events.

Leveraging biomaterials for enhancing T cell immunotherapy.

The dynamic roles of T cells in the immune system to recognize and destroy the infected or mutated cells render T cell therapy a prospective treatment for a variety of diseases including cancer, autoimmune diseases, and allograft rejection. However, the clinical applications of T cell therapy remain unsatisfactory due to the tedious manufacturing process, off-target cytotoxicity, poor cell persistence, and associated adverse effects. To this end, various biomaterials have been introduced to enhance T cell therapy by facilitating proliferation, enhancing local enrichment, prolonging retention, and alleviating side effects. This review highlights the design strategies of biomaterials developed for T cell expansion, enrichment, and delivery as well as their corresponding therapeutic effects. The prospects of biomaterials for enhancing T cell immunotherapy are also discussed in this review.