A generic coordination assembly-enabled nanocoating of individual tumor cells for personalized immunotherapy

A generic and effective tumor cells encapsulation strategy enabled by metal–organic coordination is developed to prepare a vaccine for personalized immunotherapy. Specifically, an epigallocatechin‐3‐gallate (EGCG)‐Al(III) coordination layer is in situ formed onto individual living cells in aqueous phase and the process can be completed within an hour. 98% of proteins in the cells are entrapped within the microparticles, which are endowed with high antigens loading capacity. The microparticles enhance the uptake efficiency of antigens, protect antigens from degradation in vivo, and delay the retention time of antigens in the lymph nodes. Moreover, dendritic cells (DCs) activation is triggered by the microparticles, and simultaneously, the expression of costimulation marker on DCs and the production of Th1‐related cytokines are significantly upregulated. Moreover, six kinds of tumor cells are utilized and successfully coated with the EGCG/Al(III) layer, suggesting the generalization of this strategy. More importantly, the microparticles exhibit a comparative antitumor effect with polyinosinic–polycytidylic acid (PolyI:C) in B16 pulmonary metastasis model. Overall, the encapsulation strategy enabled by metal–organic coordination can be potentially useful for personalized immunotherapy customized to individual patient's tumor cells

Dendritic Cells Pulsed with Exosomes in Combination with PD-1 Antibody Increase the Efficacy of Sorafenib in Hepatocellular Carcinoma Model

Advanced hepatocellular carcinoma (HCC) has limited therapeutic options. Immunotherapy is a promising treatment, while sorafenib is a first-line drug-based treatment for advanced HCC. However, the efficacy of sorafenib and immunotherapy in combination, have not been clearly evaluated. Sorafenib treatment has been shown to promote immunosuppression by increasing hypoxia in orthotopic HCC models. Here, we found that sorafenib treatment in mice with orthotopic HCC increased the expression of inhibitor programmed death-ligand 1 (PD-L1) and T-regulatory cells in tumor tissues. We pulsed dendritic cells with exosomes derived from tumor cells (DC-TEX) and found that the number of T-regulatory cells decreased and the number of CD8+T cells increased. However, combining DC-TEX and sorafenib did not prolong survival in these mice. Moreover, we found that the number of PD-1+CD8+T cells significantly increased after DC-TEX treatment. Therefore, we next added PD-1 antibody (PD-1 Ab) to the treatment regimen to block the PD-1/PD-L1 pathway, and found that the exhausted CD8+T cells were restored, without affecting the number of T-regulatory cells. Thus, our data suggest that the combination of DC-TEX and PD-1 Ab enhanced the efficacy of sorafenib, but treatment with either DC-TEX or PD-1 Ab alone, did not

Supramolecular co-assembly of self-adjuvanting nanofibrious peptide hydrogel enhances cancer vaccination by activating MyD88-dependent NF-κB signaling pathway without inflammation

Peptide vaccine targeting tumor-specific antigens is a promising cancer treatment regimen. However, peptide vaccines are commonly low-immunogenic, leading to suboptimal antitumor T-cell responses. Current peptide vaccination approaches are challenged by the variability of peptide physicochemical characters and vaccine formulations, flexibility, and the broad feasibility. Here, the supramolecular co-assembly of antigen epitope-conjugated peptides (ECPs) targeting CD8 or CD4 T-cell receptors was used to engineer a nanofibrious hydrogel vaccine platform. This approach provided precise and tunable loading of peptide antigens in nanofibers, which notably increased the antigen uptake, cross-presentation, and activation of dendritic cells (DCs). Immunization in mice indicated that the co-assembled peptide hydrogel did not induce local inflammation responses and elicited significantly promoted T-cell immunity by activating the MyD88-dependent NF-κB signaling pathway in DCs. Vaccination of mice using co-assembled peptide vaccine stimulated both enhanced CD8 and CD4 T cells against EG.7-OVA tumors without additional immunoadjuvants or delivery systems, and resulted in a more remarkable cancer immunotherapy efficacy, compared with free peptide vaccine or aluminum-adjuvanted peptide formulation. Altogether, peptide co-assembly demonstrated by three independent pairs of ECPs is a facile, customizable, and chemically defined approach for co-delivering peptide antigens in self-adjuvanting hydrogel vaccines that could induce stronger anticancer T-cell responses

Synergy of antioxidant and M2 polarization in polyphenol‐modified konjac glucomannan dressing for remodeling wound healing microenvironment

Abstract Effective skin wound healing and tissue regeneration remain a challenge. Excessive/chronic inflammation inhibits wound healing, leading to scar formation. Herein, we report a wound dressing composed of KGM‐GA based on the natural substances konjac glucomannan (KGM) and gallic acid (GA) that accelerates wound healing without any additional drugs. An in vitro study showed that KGM‐GA could not only stimulate macrophage polarization to the anti‐inflammatory M2 phenotype but also decrease reactive oxygen species (ROS) levels, indicating excellent anti‐inflammatory properties. Moreover, in vivo studies of skin wounds demonstrated that the KGM‐GA dressing significantly improved wound healing by accelerating wound closure, collagen deposition, and angiogenesis. In addition, it was observed that KGM‐GA regulated M2 polarization, reducing the production of intracellular ROS in the wound microenvironment, which was consistent with the in vitro experiments. Therefore, this study designed a multifunctional biomaterial with biological activity, providing a novel dressing for wound healing

Macrophage metabolism reprogramming EGCG-Cu coordination capsules delivered in polyzwitterionic hydrogel for burn wound healing and regeneration

Excessive reactive oxygen species (ROS) at severe burn injury sites may promote metabolic reprogramming of macrophages to induce a deteriorative and uncontrolled inflammation cycle, leading to delayed wound healing and regeneration. Here, a novel bioactive, anti-fouling, flexible polyzwitterionic hydrogel encapsulated with epigallocatechin gallate (EGCG)-copper (Cu) capsules (termed as EGCG-Cu@CBgel) is engineered for burn wound management, which is dedicated to synergistically exerting ROS-scavenging, immune metabolic regulation and pro-angiogenic effects. EGCG-Cu@CBgel can scavenge ROS to normalize intracellular redox homeostasis, effectively relieving oxidative damages and blocking proinflammatory signal transduction. Importantly, EGCG-Cu can inhibit the activity of hexokinase and phosphofructokinase, alleviate accumulation of pyruvate and convert it to acetyl coenzyme A (CoA), whereby inhibits glycolysis and normalizes tricarboxylic acid (TCA) cycle. Additionally, metabolic reprogramming of macrophages by EGCG-Cu downregulates M1-type polarization and the expression of proinflammatory cytokines both in vitro and in vivo. Meanwhile, copper ions (Cu2+) released from the hydrogel facilitate angiogenesis. EGCG-Cu@CBgel significantly accelerates the healing of severe burn wound via promoting wound closure, weakening tissue-damaging inflammatory responses and enhancing the remodeling of pathological structure. Overall, this study demonstrates the great potential of bioactive hydrogel dressing in treating burn wounds without unnecessary secondary damage to newly formed skin, and highlights the importance of immunometabolism modulation in tissue repair and regeneration

Bio-orthogonal click reaction-enabled highly specific in situ cellularization of tissue engineering scaffolds

10.1016/j.biomaterials.2019.119615Biomaterials23

Supramolecular Polymer‐Nanomedicine Hydrogel Loaded with Tumor Associated Macrophage‐Reprogramming polyTLR7/8a Nanoregulator for Enhanced Anti‐Angiogenesis Therapy of Orthotopic Hepatocellular Carcinoma

Abstract Anti‐angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro‐angiogenic factors in the tumor microenvironment (TME) in response to anti‐angiogenic therapy, recruiting tumor‐associated macrophages (TAMs), leading to revascularization and tumor progression. To regulate cell types in TME and promote the therapeutic efficiency of anti‐angiogenic therapy, a supramolecular hydrogel drug delivery system (PLDX‐PMI) co‐assembled by anti‐angiogenic nanomedicines (PCN‐Len nanoparticles (NPs)) and oxidized dextran (DX), and loaded with TAMs‐reprogramming polyTLR7/8a nanoregulators (p(Man‐IMDQ) NRs) is developed for orthotopic liver cancer therapy. PCN‐Len NPs target tyrosine kinases of vascular endothelial cells and blocked VEGFR signaling pathway. p(Man‐IMDQ) NRs repolarize pro‐angiogenic M2‐type TAMs into anti‐angiogenic M1‐type TAMs via mannose‐binding receptors, reducing the secretion of VEGF, which further compromised the migration and proliferation of vascular endothelial cells. On highly malignant orthotopic liver cancer Hepa1‐6 model, it is found that a single administration of the hydrogel formulation significantly decreases tumor microvessel density, promotes tumor vascular network maturation, and reduces M2‐subtype TAMs, thereby effectively inhibiting tumor progression. Collectively, findings in this work highlight the great significance of TAMs reprogramming in enhancing anti‐angiogenesis treatment for orthotopic HCC, and provides an advanced hydrogel delivery system‐based synergistic approach for tumor therapy

A Light Responsive Nanoparticle-Based Delivery System Using Pheophorbide A Graft Polyethylenimine for Dendritic Cell-Based Cancer Immunotherapy

In this study, the photochemical internalization (PCI) technique was adopted in a nanoparticle-based antigen delivery system to enhance antigen-specific CD8⁺ T cell immune response for cancer immunotherapy. Pheophorbide A, a hydrophobic photosensitizer, grafted with polyethylenimine (PheoA-PEI) with endosome escape activity and near-infrared imaging capability was prepared. A model antigen ovalbumin (OVA) was then complexed with PheoA-PEI to form PheoA-PEI/OVA nanoparticles (PheoA-PEI/OVA NPs) that are responsive to light. Flow cytometry analysis revealed increased endocytosis in a murine dendritic cell line (DC2.4) that was treated with PheoA-PEI/OVA NPs compared to free OVA. Generation of reactive oxygen species (ROS) in DC2.4 cells was also confirmed quantitatively and qualitatively using 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA). Confocal laser scanning microscopy (CLSM) further demonstrated that the PheoA-PEI/OVA NPs enhanced cytosolic antigen release after light stimulation. Moreover, PheoA-PEI/OVA NP treated DC2.4 cells exhibited enhanced cross-presentation to B3Z T cell hybridoma <i>in vitro</i> after light irradiation, substantially increased compared to those treated with free OVA. Consistently, <i>in vivo</i> results revealed upregulation of CD3⁺CD8⁺T lymphocytes in tumors of mice treated with dendritic cells plus PheoA-PEI/OVA NPs and light irradiation. The activated T cell response is partly responsible for the inhibitory effect on E.G7 tumor growth in mice immunized with dendritic cells plus PheoA-PEI/OVA NPs and light irradiation. Our results demonstrate the feasibility to enhance antigen-specific CD8⁺ T cell immune response by light-responsive nanoparticle-based vaccine delivery for cancer immunotherapy