Photo-crosslinkable hyaluronic acid microgels with reactive oxygen species scavenging capacity for mesenchymal stem cell encapsulation.

Mesenchymal stem cells (MSCs) have gained increasing attention in various biomedical applications. However, conventional therapeutic approaches, such as direct intravenous injection, are associated with low cell survival due to the shear force during injection and the oxidative stress microenvironments in the lesion area. Herein, a photo-crosslinkable antioxidant hydrogel based on tyramine- and dopamine-modified hyaluronic acid (HA-Tyr/HA-DA) was developed. Meanwhile, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were encapsulated in HA-Tyr/HA-DA hydrogel using a microfluidic system to create size-controllable microgels (hUC-MSCs@microgels). The HA-Tyr/HA-DA hydrogel was demonstrated to have good rheology, biocompatibility, and antioxidant properties for cell microencapsulation. The hUC-MSCs encapsulated in microgels showed a high viability and a significantly improved the survival rate under oxidative stress conditions. Therefore, the presented work provides a promising platform for MSCs microencapsulation, which may further improve the stem cell-based biomedical applications.

Folic acid-targeted pluronic F127 micelles improve oxidative stress and inhibit fibrosis for increasing AKI efficacy.

The oxidative stress and activation of the fibrosis pathway are essential pathological mechanisms of acute kidney injury (AKI). In this article, we designed a drug delivery system that could effectively improve oxidative stress and relieve fibrosis by the combination of precise targeting, solubilization, and reducing the toxicity of nano-transport system to strengthen the efficacy of AKI. Folic acid (FA) was used as the targeting molecule, and curcumin (Cur) and resveratrol (Res), which are Chinese medicine monomers with anti-inflammatory and antioxidant effects, were used as model drugs. Here, the targeting nanosystem (Cur/Res@FA-F127/TPGS) co-loaded with Cur and Res was successfully synthesized. Finally, the comprehensive therapeutic effect of the nanosystem was evaluated through the targeted and pharmacodynamic researches on the AKI models induced by cisplatin (CDDP) in vitro and in vivo. The studies in vitro proved that the nanosystem could not only specifically target HK-2 cells and promote the effective accumulation of Cur and Res in the kidney, but also effectively improve oxidative stress by eliminating reactive oxygen species (ROS), stabilizing mitochondrial membrane potential (MMP), and reducing the expression of apoptosis-related proteins. The studies in vivo showed that the nanosystem could effectively play the role of anti-oxidation, anti-inflammatory and alleviate fibrosis to reduce the apoptosis and necrosis of renal tubular cells. The nanosystem could coordinately repair damaged HK-2 cells by improving oxidative stress, inhibiting inflammation and tissue fibrosis, which provided a new idea for the treatment of AKI.

Co-delivery of celastrol and lutein with pH sensitive nano micelles for treating acute kidney injury.

To treat acute kidney injury with high efficiency and low toxicity, a novel nanoplatform was developed to remove excess reactive oxygen species (ROS). Lutein (LU) and celastrol (Cel) were loaded into low molecular weight chitosan (CS) to prepare Cel@LU-CA-CS nanomicelles. Renal tubular epithelial (HK-2) cell uptake experiments showed that the drugs could be internalized in renal tubular via the megalin receptor. In this study, the amide bond formed by the reaction of citraconic anhydride (CA) with an amino group of CS could be destroyed under acidic conditions. Therefore, the drugs were released in HK-2 cells due to the acidic environment of the lysosome. In vitro studies showed that the nanomicelles could reduce toxicity in non-target organs and enhance therapeutic efficacy in acute kidney injury (AKI). In addition, Cel@LU-CA-CS micelles had alleviated kidney oxidative stress disorder and stabilized the mitochondrial membrane potential quickly. Next, in vivo studies proved that Cel@LU-CA-CS micelles could inhibit the activation of the NF-κB p65 and p38 MAPK inflammatory signaling pathways. Therefore, the micelles further reduced the overexpression of related inflammatory factors. In conclusion, Cel@LU-CA-CS nanomicelles could treat AKI with high efficiency and low toxicity, and inhibit renal fibrosis.

Nanozyme-natural enzymes cascade catalyze cholesterol consumption and reverse cancer multidrug resistance.

Multidrug resistance is still a major obstacle to cancer treatment. The most studies are to inhibit the activity of the drug transporter P-glycoprotein (P-gp), but the effect is not ideal. Herein, a nanosystem was built based on cascade catalytic consumption of cholesterol. Cholesterol oxidase (natural enzyme, COD) was immobilized on the carrier (NH2-MIL-88B, MOF) through amide reaction, COD catalyzed the consumption of cholesterol, the reaction product H2O2 was further produced by the MOF with its peroxidase-like activity to produce hydroxyl radicals (•OH) with killing effect. Due to the high expression of CD44 receptor on the surface of tumor cells, we encapsulated chondroitin sulfate gel shell (CS-shell) with CD44 targeting and apoptosis promoting effect on the surface of DOX@MOF-COD nanoparticles, which can accurately and efficiently deliver the drugs to the tumor site and improve the effect of reversing drug resistance. Taking drug-resistant cell membrane as "breakthrough", this paper will provide a new idea for reversing multidrug resistance of tumor.

Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency.

Although the strategies to induce dendritic cells (DCs) maturation and promote their antigen presentation can stimulate the tumor immune response, the endogenous deficiency and immunosuppression of DCs reduce antigen utilization, which limits antigen presentation efficiency and reduces immunotherapy effectiveness. Here, we report an endogenous stimulus-responsive nanodelivery system (DOX@HFn-MSO@PGZL). On the one hand, doxorubicin (DOX) promoted antigen presentation by DCs after the immunogenic death of tumor cells. On the other hand, l-methionine sulfoximine (MSO) regulated the glutamine metabolism of tumor-associated macrophages (TAMs) to induce a shift toward the M1-type. M1-TAMs synergistically presented antigens with mature DCs and were more frequently produced to destroy the tumor suppressive immune microenvironment, resulting in the alleviation of DCs functional inhibition. Ultimately, the antigen presentation efficiency was improved, completely activating tumor immunity and exhibiting powerful antitumor effects.

Chemotherapy based on "Domino-effect" combined with immunotherapy amplifying the efficacy of an anti-metastatic treatment.

In tumor immunotherapy, Treg cells are immunosuppressive cells. In general, the main strategy of chemo immune-therapy for Treg cells is to eliminate them using chemotherapy drugs combined with immune checkpoint inhibitors. However, the dead Treg cells still exert immunosuppressive effects via the nucleoside adenosine pathway. To improve immunosuppression, we designed a nanosystem to deliver synthetic chemotherapeutics and immune activators. The homemade curcumin analog (CA) was encapsulated by α-lactalbumin (α-LA), and the Treg cell specific antibody (mAb), as a therapeutic agent, was linked to the drug-loaded protein via matrix metalloproteinase-responded peptide (P). After the cleavage peptide responded to matrix metalloproteinase (MMP-2), the CA@α-LA-P-mAb nanoparticles were separated into CA@α-LA and antibody, which can specifically enter cancer cells and Treg cells via membrane fusion and Nrp-1 receptors, respectively. Finally, we found that CA can not only lead to cell death by the chondriosome apoptosis approach but also reduce the production of Treg cells by inhibiting the expression of foxp3 (a key transcription factor of Treg cells). In addition, specific antibodies can improve the immunosuppression of existing Treg cells. The combined effect of CA and antibodies amplifies the role of chemotherapy in metastatic breast cancer.