bims-engexo Biomed News
on Engineered exosomes
Issue of 2024–09–15
thirteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur
  1. Exosome-mediated renal protection: Halting the progression of fibrosis.
  2. Injectable Alginate-Based Hydrogels Encapsulating Engineered Endothelial Extracellular Vesicles for the Treatment of Critical Limb Ischemia.
  3. Engineering exosomes derived from TNF-α preconditioned IPFP-MSCs enhance both yield and therapeutic efficacy for osteoarthritis.
  4. SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-β signaling pathway.
  5. Innovative Therapeutic Delivery of Metastasis-Associated in Colon Cancer 1-Suppressing miRNA Using High Transmembrane 4 L6 Family Member 5-Targeting Exosomes in Colorectal Cancer Mouse Models.
  6. Advancements of engineered live oncolytic biotherapeutics (microbe/virus/cells): Preclinical research and clinical progress.
  7. Engineered Macrophage Membrane-Coated S100A9-siRNA for Ameliorating Myocardial Ischemia-Reperfusion Injury.
  8. Astragalus polysaccharide enhances antitumoral effects of chimeric antigen receptor- engineered (CAR) T cells by increasing CD122+CXCR3+PD-1- memory T cells.
  9. Urine-derived stem cells serve as a robust platform for generating native or engineered extracellular vesicles.
  10. Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder.
  11. Engineered model of heart tissue repair for exploring fibrotic processes and therapeutic interventions.
  12. Engineered PLGA Core-Lipid Shell Hybrid Nanocarriers Improve the Efficacy and Safety of Irinotecan to Combat Colon Cancer.
  13. IL23R-specific CAR Tregs for the treatment of Crohn's disease.
  1. Genes Dis. 2024 Nov;11(6): 101117
    Exosome-mediated renal protection: Halting the progression of fibrosis.
    Chuanqi Liu, Qingfeng Li, Jian-Xing Ma, Baisong Lu, Tracy Criswell, Yuanyuan Zhang.
      Renal fibrosis is a complex and multifactorial process that involves inflammation, cell proliferation, collagen, and fibronectin deposition in the kidney, ultimately leading to chronic kidney disease and even end-stage renal disease. The main goal of treatment is to slow down or halt the progression of fibrosis and to improve or preserve kidney function. Despite significant progress made in understanding the underlying mechanisms of renal fibrosis, current therapies have limited renal protection as the disease progresses. Exosomes derived from stem cells are a newer area of research for the treatment of renal fibrosis. Exosomes as nano-sized extracellular vesicles carry proteins, lipids, and nucleic acids, which can be taken up by local or distant cells, serving as mediators of intercellular communication and as drug delivery vehicles. Exosomes deliver molecules that reduce inflammation, renal fibrosis and extracellular matrix protein production, and promote tissue regeneration in animal models of kidney disease. Additionally, they have several advantages over stem cells, such as being non-immunogenic, having low risk of tumor formation, and being easier to produce and store. This review describes the use of natural and engineered exosomes containing therapeutic agents capable of mediating anti-inflammatory and anti-fibrotic processes during both acute kidney injury and chronic kidney disease. Exosome-based therapies will be compared with stem cell-based treatments for tissue regeneration, with a focus on renal protection. Finally, future directions and strategies for improving the therapeutic efficacy of exosomes are discussed.
    Keywords:  Chronic kidney disease; Exosomes; Growth factors; Renal fibrosis; Stem cells
    DOI:  https://doi.org/10.1016/j.gendis.2023.101117
  2. Biomacromolecules. 2024 Sep 12.
    Injectable Alginate-Based Hydrogels Encapsulating Engineered Endothelial Extracellular Vesicles for the Treatment of Critical Limb Ischemia.
    Fei Fang, Hanqiao Yang, Chunli Li, Jie Ren, Xinyi Lin, Jing Xie, Xiaoheng Liu.
      Critical limb ischemia (CLI) is a peripheral arterial disease resulting from chronic inflammation of vascular systems. Recent studies have shown that inhibiting macrophage inflammation has the potential to treat CLI, and extracellular vesicles (EVs) from endothelial cells can inhibit macrophage activation. However, the limited cell-targeting capabilities and rapid clearance of EVs from the injection site limit the in vivo application of the EVs. Here, we modified endothelial EVs with platelet membranes (pM/EVs) to boost the inhibition effects on macrophage inflammation and developed an injectable alginate-based collagen composite (ACC) hydrogel for localized delivery of pM/EVs (pM/EVs@ACC) for CLI treatment. We found that pM/EVs can effectively inhibit macrophage inflammation in vitro. Furthermore, pM/EVs@ACC treatment significantly promotes the recovery of limb functions, restoring the feet' blood supply and relieving inflammation. Our findings provide compelling evidence that the pM/EVs@ACC injectable system mediating delivery of pM/EVs is a promising strategy for CLI treatment.
    DOI:  https://doi.org/10.1021/acs.biomac.4c00845
  3. J Nanobiotechnology. 2024 Sep 11. 22(1): 555
    Engineering exosomes derived from TNF-α preconditioned IPFP-MSCs enhance both yield and therapeutic efficacy for osteoarthritis.
    Jiangyi Wu, Jinhui Wu, Wei Xiang, Yunquan Gong, Daibo Feng, Shunzheng Fang, Yaran Wu, Zheng Liu, Yang Li, Ran Chen, Xiaoqi Zhang, Bingfei Li, Lifeng Chen, Runze Jin, Song Li, Bin Zhang, Tongyi Zhang, Lin Yin, Yizhao Zhou, Shu Huang, Ningning Liu, Hao Xu, Jiqin Lian, Yongqian Wang, Siru Zhou, Zhenhong Ni.
       BACKGROUND: The pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA.
    METHODS: The exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF-α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis.
    RESULTS: The preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF-α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF-α, thereby exerting chondroprotective effects.
    CONCLUSION: TNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA.
    Keywords:  Chondrocytes; Exosomes; Mesenchymal stem cells; Osteoarthritis; TNF-α precondition
    DOI:  https://doi.org/10.1186/s12951-024-02795-9
  4. FASEB J. 2024 Sep;38(17): e70011
    SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-β signaling pathway.
    Hongyu Chen, Xiaoyong Wu, Yinan Lan, Xijie Zhou, Ye Zhang, Long Long, Yuliang Zhong, Zhengan Hao, Weijun Zhang, DeTing Xue.
      In clinical settings, addressing large bone defects remains a significant challenge for orthopedic surgeons. The use of genetically modified bone marrow mesenchymal stem cells (BMSCs) has emerged as a highly promising approach for these treatments. Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a multifunctional secreted glycoprotein, the role of which remains unclear in human hBMSCs. This study used various experimental methods to elucidate the potential mechanism by which SCUBE3 influences osteogenic differentiation of hBMSCs in vitro. Additionally, the therapeutic efficacy of SCUBE3, in conjunction with porous GeLMA microspheres, was evaluated in vivo using a mouse bone defect model. Our findings indicate that SCUBE3 levels increase significantly during early osteogenic differentiation of hBMSCs, and that reducing SCUBE3 levels can hinder this differentiation. Overexpressing SCUBE3 elevated osteogenesis gene and protein levels and enhanced calcium deposition. Furthermore, treatment with recombinant human SCUBE3 (rhSCUBE3) protein boosted BMP2 and TGF-β expression, activated mitophagy in hBMSCs, ameliorated oxidative stress, and restored osteogenic function through SMAD phosphorylation. In vivo, GELMA/OE treatment effectively accelerated bone healing in mice. In conclusion, SCUBE3 fosters osteogenic differentiation and mitophagy in hBMSCs by activating the BMP2/TGF-β signaling pathway. When combined with engineered hydrogel cell therapy, it could offer valuable guidance for the clinical management of extensive bone defects.
    Keywords:  BMP2; HBMSCs; SCUBE3; TGF‐β; mitophagy; osteogenic differentiation
    DOI:  https://doi.org/10.1096/fj.202400991R
  5. Int J Mol Sci. 2024 Aug 26. pii: 9232. [Epub ahead of print]25(17):
    Innovative Therapeutic Delivery of Metastasis-Associated in Colon Cancer 1-Suppressing miRNA Using High Transmembrane 4 L6 Family Member 5-Targeting Exosomes in Colorectal Cancer Mouse Models.
    Byung-Jo Choi, Dosang Lee, Jung Hyun Park, Tae Ho Hong, Ok-Hee Kim, Sang Chul Lee, Kee-Hwan Kim, Ho Joong Choi, Say-June Kim.
      Elevated metastasis-associated in colon cancer 1 (MACC1) expression in colorectal cancer patients, and high transmembrane 4 L6 family member 5 (TM4SF5) protein expressed on various solid tumors' surface, are linked to aggressive cancer behavior and progression. In this study, adipose-derived stem cells (ASCs) were engineered to produce exosomes (Ex) that target the TM4SF5 protein on tumors. Moreover, MACC1-targeting microRNA was encapsulated within the Ex, resulting in TM4SF5-targeting Ex (MACC1-suppressing miRNA; miR-143). The anticancer effects of these Ex were investigated in vitro using the human colorectal cell line HCT116 and in vivo using colorectal cancer mouse xenograft models. In the in vivo assessment, administration of TM4SF5-targeting Ex[miR-143], referred to as tEx[miR-143] herein, resulted in the smallest tumor size, the lowest tumor growth rate, and the lightest excised tumors compared to other treatments (p < 0.05). It also led to the decreased expression of MACC-1 and anti-apoptotic markers MCL-1 and Bcl-xL while inducing the highest expression of pro-apoptotic markers BAX and BIM. These results were consistent with in vitro findings, where t Ex[miR-143] demonstrated the highest inhibition of HCT116 cell migration and invasion. These findings highlight the potential of tEx[miR-143] as an effective therapeutic strategy for colorectal cancer, demonstrating promising results in both targetability and anti-tumor effects in vitro and in vivo, warranting further investigation in clinical settings.
    Keywords:  MACC1; TM4SF5 protein; colorectal cancer; exosome; microRNA; targeted therapy
    DOI:  https://doi.org/10.3390/ijms25179232
  6. J Control Release. 2024 Sep 11. pii: S0168-3659(24)00608-4. [Epub ahead of print]375 209-235
    Advancements of engineered live oncolytic biotherapeutics (microbe/virus/cells): Preclinical research and clinical progress.
    Zhengzhuo Qi, Junmou Gu, Lihang Qu, Xianbao Shi, Zhonggui He, Jin Sun, Lingchen Tan, Mengchi Sun.
      The proven efficacy of immunotherapy in fighting tumors has been firmly established, heralding a new era in harnessing both the innate and adaptive immune systems for cancer treatment. Despite its promise, challenges such as inefficient delivery, insufficient tumor penetration, and considerable potential toxicity of immunomodulatory agents have impeded the advancement of immunotherapies. Recent endeavors in the realm of tumor prophylaxis and management have highlighted the use of living biological entities, including bacteria, oncolytic viruses, and immune cells, as a vanguard for an innovative class of live biotherapeutic products (LBPs). These LBPs are gaining recognition for their inherent ability to target tumors. However, these LBPs must contend with significant barriers, including robust immune clearance mechanisms, cytotoxicity and other in vivo adverse effects. Priority must be placed on enhancing their safety and therapeutic indices. This review consolidates the latest preclinical research and clinical progress pertaining to the exploitation of engineered biologics, spanning bacteria, oncolytic viruses, immune cells, and summarizes their integration with combination therapies aimed at circumventing current clinical impasses. Additionally, the prospective utilities and inherent challenges of the biotherapeutics are deliberated, with the objective of accelerating their clinical application in the foreseeable future.
    Keywords:  Clinical trials; Engineered live oncolytic biotherapeutics; Immune cells; Oncolytic viruses; bacteria
    DOI:  https://doi.org/10.1016/j.jconrel.2024.09.006
  7. Adv Sci (Weinh). 2024 Sep 12. e2403542
    Engineered Macrophage Membrane-Coated S100A9-siRNA for Ameliorating Myocardial Ischemia-Reperfusion Injury.
    He Lu, Junzhuo Wang, Ziwei Chen, Jing Wang, Yaohui Jiang, Zequn Xia, Ya Hou, Pingping Shang, Rutian Li, Yuyong Liu, Jun Xie.
      Despite the widespread adoption of emergency coronary reperfusion therapy, reperfusion-induced myocardial injury remains a challenging issue in clinical practice. Following myocardial reperfusion, S100A8/A9 molecules are considered pivotal in initiating and regulating tissue inflammatory damage. Effectively reducing the S100A8/A9 level in ischemic myocardial tissue holds significant therapeutic value in salvaging damaged myocardium. In this study, HA (hemagglutinin)- and RAGE (receptor for advanced glycation end products)- comodified macrophage membrane-coated siRNA nanoparticles (MMM/RNA NPs) with siRNA targeting S100A9 (S100A9-siRNA) are successfully prepared. This nanocarrier system is able to target effectively the injured myocardium in an inflammatory environment while evading digestive damage by lysosomes. In vivo, migration of MMM/RNA NPs to myocardial injury lesions is confirmed in a myocardial ischemia-reperfusion injury (MIRI) mouse model. Intravenous injection of MMM/RNA NPs significantly reduced S100A9 levels in serum and myocardial tissues, further decreasing myocardial infarction area and improving cardiac function. Targeted reduction of S100A8/A9 by genetically modified macrophage membrane-coated nanoparticles may represent a new therapeutic intervention for MIRI.
    Keywords:  S100A8 / A9; engineered macrophage membrane; myocardial ischemia‐reperfusion injury; neutrophils; siRNA
    DOI:  https://doi.org/10.1002/advs.202403542
  8. Biomed Pharmacother. 2024 Sep 06. pii: S0753-3322(24)01286-1. [Epub ahead of print]179 117401
    Astragalus polysaccharide enhances antitumoral effects of chimeric antigen receptor- engineered (CAR) T cells by increasing CD122+CXCR3+PD-1- memory T cells.
    Qunfang Zhang, Chunzhao Su, Yini Luo, Fang Zheng, Chun-Ling Liang, Yuchao Chen, Huazhen Liu, Feifei Qiu, Yunshan Liu, Wenxuan Feng, Zhenhua Dai.
      Chimeric antigen receptor-engineered T (CAR-T) cell therapy of cancer has been a hotspot and promising. However, due to rapid exhaustion, CAR-T cells are less effective in solid tumors than in hematological ones. CD122+CXCR3+ memory T cells are characterized with longevity, self-renewal and great antitumoral capacity. Thus, it's compelling to induce memory CAR-T cells to enhance their efficacy on solid tumors. Astragalus polysaccharide (APS) has reportedly exhibited antitumoral effects. However, it's unclear if APS has an impact on CD8+ memory T cell generation or persistence. Using two human cancer cell lines, here we found that APS significantly improved the persistence of GPC3-targeted CAR-T cells and enhanced their suppression of tumor growth in both Huh7 and HepG2 xenograft models of hepatocellular carcinoma. APS increased CD122+/CXCR3+ memory T cells, but decreased their PD-1+ subset within CD8+ CAR-T cells in tumor-bearing mice, while these effects of APS were also confirmed with in vitro experiments. Moreover, APS augmented the expression of chemokines CXCL9/CXCL10 by the tumor in vivo and in vitro. It also enhanced the proliferation and chemotaxis/migration of CAR-T cells in vitro. Finally, APS promoted the phosphorylation of STAT5 in CD8+ CAR-T cells, whereas inhibition of STAT5 activation reversed these in vitro effects of APS. Therefore, APS enhanced the antitumoral effects of CD8+ CAR-T cells by promoting formation/persistence of CD122+/CXCR3+/PD-1- memory T cells and their migration to the tumor.
    Keywords:  Astragalus polysaccharide; CAR-T; CXCR3; Hepatocellular carcinoma; Memory T cell; PD-1
    DOI:  https://doi.org/10.1016/j.biopha.2024.117401
  9. Stem Cell Res Ther. 2024 Sep 11. 15(1): 288
    Urine-derived stem cells serve as a robust platform for generating native or engineered extracellular vesicles.
    Anders Toftegaard Boysen, Bradley Whitehead, Anne Louise S Revenfeld, Dhanu Gupta, Thor Petersen, Peter Nejsum.
       BACKGROUND: Mesenchymal stromal cell (MSC) therapy holds great potential yet efficacy and safety concerns with cell therapy persist. The beneficial effects of MSCs are often attributed to their secretome that includes extracellular vesicles (EVs). EVs carry biologically active molecules, protected by a lipid bilayer. However, several barriers hinder large-scale MSC EV production. A serum-free culturing approach is preferred for producing clinical-grade MSC-derived EVs but this can affect both yield and purity. Consequently, new strategies have been explored, including genetically engineering MSCs to alter EV compositions to enhance potency, increase circulation time or mediate targeting. However, efficient transfection of MSCs is challenging. Typical sources of MSC include adipose tissue and bone marrow, which both require invasive extraction procedures. Here, we investigate the use of urine-derived stem cells (USCs) as a non-invasive and inexhaustible source of MSCs for EV production.
    METHODS: We isolated, expanded, and characterized urine-derived stem cells (USCs) harvested from eight healthy donors at three different time points during the day. We evaluated the number of clones per urination, proliferation capacity and conducted flow cytometry to establish expression of surface markers. EVs were produced in chemically defined media and characterized. PEI/DNA transfection was used to genetically engineer USCs using transposon technology.
    RESULTS: There were no differences between time points for clone number, doubling time or viability. USCs showed immunophenotypic characteristics of MSCs, such as expression of CD73, CD90 and CD105, with no difference at the assessed time points, however, male donors had reduced CD73 + cells. Expanded USCs were incubated without growth factors or serum for 72 h without a loss in viability and EVs were isolated. USCs were transfected with high efficiency and after 10 days of selection, pure engineered cell cultures were established.
    CONCLUSIONS: Isolation and expansion of MSCs from urine is non-invasive, robust, and without apparent sex-related differences. The sampling time point did not affect any measured markers or USC isolation potential. USCs offer an attractive production platform for EVs, both native and engineered.
    Keywords:  Extracellular vesicles; MSC-engineering; Noninvasive; Urine-derived stem cells
    DOI:  https://doi.org/10.1186/s13287-024-03903-0
  10. Nat Commun. 2024 Sep 08. 15(1): 7853
    Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder.
    Timothy F Shay, Seongmin Jang, Tyler J Brittain, Xinhong Chen, Beth Walker, Claire Tebbutt, Yujie Fan, Damien A Wolfe, Cynthia M Arokiaraj, Erin E Sullivan, Xiaozhe Ding, Ting-Yu Wang, Yaping Lei, Miguel R Chuapoco, Tsui-Fen Chou, Viviana Gradinaru.
      Adeno-associated viruses (AAVs) are foundational gene delivery tools for basic science and clinical therapeutics. However, lack of mechanistic insight, especially for engineered vectors created by directed evolution, can hamper their application. Here, we adapt an unbiased human cell microarray platform to determine the extracellular and cell surface interactomes of natural and engineered AAVs. We identify a naturally-evolved and serotype-specific interaction between the AAV9 capsid and human interleukin 3 (IL3), with possible roles in host immune modulation, as well as lab-evolved low-density lipoprotein receptor-related protein 6 (LRP6) interactions specific to engineered capsids with enhanced blood-brain barrier crossing in non-human primates after intravenous administration. The unbiased cell microarray screening approach also allows us to identify off-target tissue binding interactions of engineered brain-enriched AAV capsids that may inform vectors' peripheral organ tropism and side effects. Our cryo-electron tomography and AlphaFold modeling of capsid-interactor complexes reveal LRP6 and IL3 binding sites. These results allow confident application of engineered AAVs in diverse organisms and unlock future target-informed engineering of improved viral and non-viral vectors for non-invasive therapeutic delivery to the brain.
    DOI:  https://doi.org/10.1038/s41467-024-52149-0
  11. Nat Commun. 2024 Sep 12. 15(1): 7996
    Engineered model of heart tissue repair for exploring fibrotic processes and therapeutic interventions.
    Pengcheng Yang, Lihang Zhu, Shiya Wang, Jixing Gong, Jonathan Nimal Selvaraj, Lincai Ye, Hanxiao Chen, Yaoyao Zhang, Gongxin Wang, Wanjun Song, Zilong Li, Lin Cai, Hao Zhang, Donghui Zhang.
      Advancements in human-engineered heart tissue have enhanced the understanding of cardiac cellular alteration. Nevertheless, a human model simulating pathological remodeling following myocardial infarction for therapeutic development remains essential. Here we develop an engineered model of myocardial repair that replicates the phased remodeling process, including hypoxic stress, fibrosis, and electrophysiological dysfunction. Transcriptomic analysis identifies nine critical signaling pathways related to cellular fate transitions, leading to the evaluation of seventeen modulators for their therapeutic potential in a mini-repair model. A scoring system quantitatively evaluates the restoration of abnormal electrophysiology, demonstrating that the phased combination of TGFβ inhibitor SB431542, Rho kinase inhibitor Y27632, and WNT activator CHIR99021 yields enhanced functional restoration compared to single factor treatments in both engineered and mouse myocardial infarction model. This engineered heart tissue repair model effectively captures the phased remodeling following myocardial infarction, providing a crucial platform for discovering therapeutic targets for ischemic heart disease.
    DOI:  https://doi.org/10.1038/s41467-024-52221-9
  12. ACS Biomater Sci Eng. 2024 Sep 13.
    Engineered PLGA Core-Lipid Shell Hybrid Nanocarriers Improve the Efficacy and Safety of Irinotecan to Combat Colon Cancer.
    Prabhanjan S Giram, Ramakrishna Nimma, Anuradha Bulbule, Amit Singh Yadav, Mahadeo Gorain, Nalukurthi Naga Venkata Radharani, Gopal C Kundu, Baijayantimala Garnaik.
      Poly(lactide-co-glycolide) (PLGA) is a biocompatible and biodegradable copolymer that has gained high acceptance in biomedical applications. In the present study, PLGA (Mw = 13,900) was synthesized by ring-opening polymerization in the presence of a biocompatible zinc-proline initiator through a green route. Irinotecan (Ir) loaded with efficient PLGA core-lipid shell hybrid nanocarriers (lipomers, LPs) were formulated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000] (DSPE-PEG-2000), using soya lecithin, by a nanoprecipitation method, and the fabricated LPs were designated as P-DSPE-Ir and P-DSPE-PEG-Ir, respectively. The formulated LPs were further validated for their physicochemical properties and biological potential for colon cancer application. The potential delivery of a poorly water-soluble chemotherapeutic drug (Ir) was studied for the treatment of colon cancer. LPs were successfully prepared, providing controlled size (80-120 nm) and surface charge (∼ -35 mV), and the sustained release properties and cytotoxicity against CT-26 colon cancer cells were studied. The in vivo biodistribution and tumor site retention in CT-26 xenograft tumor-bearing Balb/C mice showed promising results for tumor uptake and retention for a prolonged time period. Unlike P-DSPE-Ir, the P-DSPE-PEG-Ir LP exhibited significant tumor growth delay as compared to untreated and blank formulation-treated groups in CT-26 (subcutaneous tumor model) after 4 treatments of 10 mg irinotecan/kg dose. The biocompatibility and safety of the LPs were confirmed by an acute toxicity study of the optimized formulation. Overall, this proof-of-concept study demonstrates that the PLGA-based LPs improve the efficacy and bioavailability and decrease neutropenia of Ir to combat colon cancer.
    Keywords:  CT-26; PLGA; chemotherapy; colon cancer; drug delivery; irinotecan; lipomer; neutropenia
    DOI:  https://doi.org/10.1021/acsbiomaterials.4c01260
  13. J Crohns Colitis. 2024 Sep 10. pii: jjae135. [Epub ahead of print]
    IL23R-specific CAR Tregs for the treatment of Crohn's disease.
    Yue Cui, Marion David, Laura Bouchareychas, Sandrine Rouquier, Satria Sajuthi, Marion Ayrault, Candice Navarin, Gregory Lara, Audrey Lafon, Gaëlle Saviane, Sonia Boulakirba, Alexandra Menardi, Alexandra Demory, Jihane Frikeche, Stephanie de la Forest Divonne Beghelli, Hsiaomei Heidi Lu, Celine Dumont, Tobias Abel, David Fenard, Maurus de la Rosa, Julie Gertner-Dardenne.
       BACKGROUND AND AIMS: Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn's disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. CAR (Chimeric Antigen Receptor) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, Interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active CD.
    METHODS: Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD patients.
    RESULTS: Our study showed that IL23R-CAR displayed negligible tonic signalling and strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR activation.
    CONCLUSIONS: Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD.
    Keywords:  CAR-Treg; Crohn’s disease; IBD; IL23R; cell therapy
    DOI:  https://doi.org/10.1093/ecco-jcc/jjae135
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