-
Journal of the American Chemical Society Jul 2024Synthesis of interior-functionalized dendritic macromolecules is generally tedious and labor-intensive, which has been a key factor hampering their practical...
Synthesis of interior-functionalized dendritic macromolecules is generally tedious and labor-intensive, which has been a key factor hampering their practical applications. Here, we have revisited this long-standing challenge and devised a modular and convergent platform to synthesize multifunctional dendrons with all-carbon backbones up to four generations via an functionalization strategy. Enabled by the palladium/norbornene cooperative catalysis, different functional groups can be introduced to each generation of dendrons during the dendron growth, making it convenient for systematic comparison of their properties. The utility of this versatile platform is further showcased in the internal-functionalization-dependent properties of dendrons as organogels and aggregation-induced emission materials.
PubMed: 38949482
DOI: 10.1021/jacs.4c06090 -
Small Methods Jul 2024Adverse side reactions and uncontrolled Zn dendrites growth are the dominant factors that have restricted the application of Zn ion batteries. Herein, a 3D...
Adverse side reactions and uncontrolled Zn dendrites growth are the dominant factors that have restricted the application of Zn ion batteries. Herein, a 3D self-supporting porous carbon fibers (denoted as PCFs) host is developed with "trap" effect to adjust the Zn deposition. The unique open structural design of N-doped carbon can act as the zincophilic sites to induce uniform deposition and inhibit adverse side reactions. More importantly, the porous hollow PCFs host with "trap" effect can induce Zn deposition in the fiber by adjusting the local electric field and current density, thereby increasing the specific energy density of the battery and inhibiting dendrite growth. In addition, the 3D open frameworks can regulate Zn flux to enable outstanding cycling performance at ultra-high current densities. As expected, the PCFs framework guarantees the uniform Zn plating and stripping with an outstanding stability over 6000 cycles at the current density of 40 mA cm. And the Zn@PCFs||MnO full battery shows an excellent lifespan over 1300 cycles at 2000 mA g.
PubMed: 38949412
DOI: 10.1002/smtd.202400408 -
ACS Nano Jul 2024The side reactions and dendrite growth at the interface of Zn anodes greatly limit their practical applications in Zn metal batteries. Herein, we propose a hybrid...
The side reactions and dendrite growth at the interface of Zn anodes greatly limit their practical applications in Zn metal batteries. Herein, we propose a hybrid molecular sieve-based interfacial layer (denoted as ZM) with a hierarchical porous structure for Zn metal anodes, which contains 70 vol % microporous ZSM-5 molecular sieves and 30 vol % mesoporous MCM-41 molecular sieves. Through comprehensive molecular dynamics simulations, we demonstrate that the mesopores (∼2.5 nm) of MCM-41 can limit the disordered diffusion of free water molecules and increase the wettability of the interfacial layer toward aqueous electrolytes. In addition, the micropores (∼0.56 nm) of ZSM-5 can optimize the Zn solvation structures by reducing the bonded water molecules, which simultaneously decrease the constraint force of solvated water molecules to Zn ions, thus promoting the penetrability and diffusion kinetics of Zn ions in ZM. The synergetic effects from the hybrid molecular sieves maintain a constant Zn concentration on the surface of the Zn electrode during Zn deposition, contributing to dendrite-free Zn anodes. Consequently, ZM-coated Zn electrodes achieved excellent cycling stability in both half and full cells.
PubMed: 38949082
DOI: 10.1021/acsnano.4c04632 -
Oncoimmunology 2024Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic...
Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.
Topics: Animals; Male; Prostatic Neoplasms; Antigens, Neoplasm; Mice; Dendritic Cells; Adjuvants, Immunologic; RNA, Messenger; Cancer Vaccines; Humans; Mice, Inbred C57BL; Cell Line, Tumor; mRNA Vaccines; CD8-Positive T-Lymphocytes; T-Lymphocytes; Immunotherapy; Lymphocyte Activation
PubMed: 38948931
DOI: 10.1080/2162402X.2024.2373526 -
BioRxiv : the Preprint Server For... Jun 2024About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor...
About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor growth. Despite progress in development of small molecules for treatment of mutant KRAS cancers, there is a need for a pan-RAS inhibitor that is effective against all RAS isoforms and variants and that avoids drug resistance. We have previously shown that the naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is a potent RAS degrader that can be re-engineered as a biologic therapy to induce regression of colorectal, breast, and pancreatic tumors. Here, we have developed a strategy for in vivo expression of this RAS degrader via mRNA delivery using a synthetic nonviral gene delivery platform composed of the poly(ethylene glycol)--poly(propylene sulfide) (PEG--PPS) block copolymer conjugated to a dendritic cationic peptide (PPDP2). Using this strategy, PPDP2 is shown to deliver mRNA to both human and mouse pancreatic cells resulting in RRSP gene expression, activity, and loss of cell proliferation. Further, pancreatic tumors are reduced with residual tumors lacking detectable RAS and phosphorylated ERK. These data support that mRNA-loaded synthetic nanocarrier delivery of a RAS degrader can interrupt the RAS signaling system within pancreatic cancer cells while avoiding side effects during therapy.
PubMed: 38948803
DOI: 10.1101/2024.06.11.598439 -
mutation induces tumor cell-intrinsic defects in enhancer landscape and resistance to immunotherapy.BioRxiv : the Preprint Server For... Jun 2024Cancer genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex including and ....
Cancer genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex including and . Importantly, clinical reports indicate that -mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. However, the mechanistic basis of immunotherapy resistance is unknown. Here, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring deficiency. Specifically, we show that loss caused decreased response to anti-PD1 immunotherapy associated with significantly reduced infiltration of dendritic cells (DCs) and CD4+ T cells into the tumor microenvironment (TME). Mechanistically, we show that loss in tumor cells led to profound downregulation of and other components of the innate immune system as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. We establish that this deregulation of gene expression is caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response such as type I IFN and inflammatory cytokines. Interestingly, we observed that transcription factor NF-κB binding motif was highly enriched in enhancers that lose accessibility upon deficiency. Finally, we confirmed that SMARCA4 and NF-κB co-occupy the same genomic loci on enhancers associated with and indicating a functional interplay between SMARCA4 and NF-κB. Taken together, our findings provide the mechanistic basis for the poor response of -mutant tumors to anti-PD1 immunotherapy and establish a functional link between SMARCA4 and NF-κB on innate immune and inflammatory gene expression regulation.
PubMed: 38948751
DOI: 10.1101/2024.06.18.599431 -
Cancer Innovation Feb 2024Since RNA sequencing has shown that induced pluripotent stem cells (iPSCs) share a common antigen profile with tumor cells, cancer vaccines that focus on iPSCs have made...
BACKGROUND
Since RNA sequencing has shown that induced pluripotent stem cells (iPSCs) share a common antigen profile with tumor cells, cancer vaccines that focus on iPSCs have made promising progress in recent years. Previously, we showed that iPSCs derived from leukemic cells of patients with primary T cell acute lymphoblastic leukemia (T-ALL) have a gene expression profile similar to that of T-ALL cell lines.
METHODS
Mice with T-ALL were treated with dendritic and T (DC-T) cells loaded with intact and complete antigens from T-ALL-derived iPSCs (T-ALL-iPSCs). We evaluated the safety and antitumor efficiency of autologous tumor-derived iPSC antigens by flow cytometry, cytokine release assay, acute toxicity experiments, long-term toxicity experiments, and other methods.
RESULTS
Our results indicate that complete tumor antigens from T-ALL-iPSCs could inhibit the growth of inoculated tumors in immunocompromised mice without causing acute and long-term toxicity.
CONCLUSION
T-ALL-iPSC-based treatment is safe and can be used as a potential strategy for leukemia immunotherapy.
PubMed: 38948536
DOI: 10.1002/cai2.95 -
Bioactive Materials Oct 2024Composite biomaterials comprising polylactide (PLA) and hydroxyapatite (HA) are applied in bone, cartilage and dental regenerative medicine, where HA confers...
Composite biomaterials comprising polylactide (PLA) and hydroxyapatite (HA) are applied in bone, cartilage and dental regenerative medicine, where HA confers osteoconductive properties. However, after surgical implantation, adverse immune responses to these composites can occur, which have been attributed to size and morphology of HA particles. Approaches to effectively modulate these adverse immune responses have not been described. PLA degradation products have been shown to alter immune cell metabolism (immunometabolism), which drives the inflammatory response. Accordingly, to modulate the inflammatory response to composite biomaterials, inhibitors were incorporated into composites comprised of amorphous PLA (aPLA) and HA (aPLA + HA) to regulate glycolytic flux. Inhibition at specific steps in glycolysis reduced proinflammatory (CD86CD206) and increased pro-regenerative (CD206) immune cell populations around implanted aPLA + HA. Notably, neutrophil and dendritic cell (DC) numbers along with proinflammatory monocyte and macrophage populations were decreased, and Arginase 1 expression among DCs was increased. Targeting immunometabolism to control the proinflammatory response to biomaterial composites, thereby creating a pro-regenerative microenvironment, is a significant advance in tissue engineering where immunomodulation enhances osseointegration and angiogenesis, which could lead to improved bone regeneration.
PubMed: 38948254
DOI: 10.1016/j.bioactmat.2024.05.046 -
Cancer Innovation Aug 2024Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene...
BACKGROUND
Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer.
METHODS
We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed.
RESULTS
Gap junction beta-2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta-2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta-2 are rare in breast cancer. The gap junction beta-2 transcription level in the p110α subunit of the phosphoinositide 3-kinase mutant subgroup was higher than that in the wild-type subgroup. Gap junction beta-2 was associated with the phosphoinositide 3-kinase-Akt signaling pathway, extracellular matrix-receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta-2 overexpression may be associated with phosphoinositide 3-kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells.
CONCLUSIONS
Gap junction beta-2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.
PubMed: 38948248
DOI: 10.1002/cai2.128 -
Cancer Innovation Jun 2024Cancer-targeted T-cell receptor T (TCR-T) cells hold promise in treating cancers such as hematological malignancies and breast cancers. However, approaches to obtain...
Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires.
BACKGROUND
Cancer-targeted T-cell receptor T (TCR-T) cells hold promise in treating cancers such as hematological malignancies and breast cancers. However, approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.
METHODS
Here, we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints. Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells, and then the expanded cells were applied to establish humanized mice. The human immune system was evaluated according to the kinetics of dendritic cells, monocytes, T-cell subsets, and cytokines. To fully stimulate the immune response and to obtain B-cell precursor NAML-6- and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells, we used the inactivated cells above to treat humanized mice twice a day every 7 days. Then, human T cells were processed for TCR β-chain (TRB) sequencing analysis. After the repertoires had been constructed, features such as the fraction, diversity, and immune signature were investigated.
RESULTS
The results demonstrated an increase in diversity and clonality of T cells after treatment. The preferential usage and features of TRBV, TRBJ, and the V-J combination were also changed. The stress also induced highly clonal expansion. Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.
CONCLUSIONS
We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools. Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells. It therefore has the potential to greatly benefit cancer treatment.
PubMed: 38947755
DOI: 10.1002/cai2.118