bims-engexo 2024-09-08 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2024–09–08
thirteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineered nanoparticles for precise targeted drug delivery and enhanced therapeutic efficacy in cancer immunotherapy.
Engineered exosome therapeutics for neurodegenerative diseases.
Emerging trends in virus and virus-like particle gene therapy delivery to the brain.
Next-Generation Therapeutic Antibodies for Cancer Treatment: Advancements, Applications, and Challenges.
Organelle Specific Macrophage Engineered Vesicles Differentially Reprogram Macrophage Polarization.
Ligand-free biodegradable poly(beta-amino ester) nanoparticles for targeted systemic delivery of mRNA to the lungs.
Lipopolymer/siRNA Complexes Engineered for Optimal Molecular and Functional Response with Chemotherapy in FLT3-Mutated Acute Myeloid Leukemia.
Synthetic Biology-Driven Microbial Therapeutics for Disease Treatment.
Nanomaterial combined engineered bacteria for intelligent tumor immunotherapy.
Gene-Engineered Cerium-Exosomes Mediate Atherosclerosis Therapy Through Remodeling of the Inflammatory Microenvironment and DNA Damage Repair.
RNA-Activatable Near-Infrared Photosensitizer for Cancer Therapy.
Unconstrained precision mitochondrial genome editing with αDdCBEs.
Overexpression of a Designed Mutant Oxyanion Binding Protein ModA/WtpA in Acidithiobacillus ferrooxidans for the Low pH Recovery of Molybdenum and Rhenium.

Acta Pharm Sin B. 2024 Aug;14(8): 3432-3456

Engineered nanoparticles for precise targeted drug delivery and enhanced therapeutic efficacy in cancer immunotherapy.

Xueqiang Peng, Jianjun Fang, Chuyuan Lou, Liang Yang, Shaobo Shan, Zixian Wang, Yutong Chen, Hangyu Li, Xuexin Li.

  The advent of cancer immunotherapy has imparted a transformative impact on cancer treatment paradigms by harnessing the power of the immune system. However, the challenge of practical and precise targeting of malignant cells persists. To address this, engineered nanoparticles (NPs) have emerged as a promising solution for enhancing targeted drug delivery in immunotherapeutic interventions, owing to their small size, low immunogenicity, and ease of surface modification. This comprehensive review delves into contemporary research at the nexus of NP engineering and immunotherapy, encompassing an extensive spectrum of NP morphologies and strategies tailored toward optimizing tumor targeting and augmenting therapeutic effectiveness. Moreover, it underscores the mechanisms that NPs leverage to bypass the numerous obstacles encountered in immunotherapeutic regimens and probes into the combined potential of NPs when co-administered with both established and novel immunotherapeutic modalities. Finally, the review evaluates the existing limitations of NPs as drug delivery platforms in immunotherapy, which could shape the path for future advancements in this promising field.

Keywords:  Blood–brain barrier; Cancer; Cancer immunotherapy; Drug delivery; Engineered nanoparticles; Nanomaterial; Nanomedicine; Tumor-barrier

DOI:  https://doi.org/10.1016/j.apsb.2024.05.010
Life Sci. 2024 Aug 28. pii: S0024-3205(24)00609-X. [Epub ahead of print]356 123019

Engineered exosome therapeutics for neurodegenerative diseases.

Biplob Saikia, Anandh Dhanushkodi.

  An increase in life expectancy comes with a higher risk for age-related neurological and cognitive dysfunctions. Given the psycho-socioeconomic burden due to unhealthy aging in the coming decades, the United Nations has declared 2021-2030 as a decade of healthy aging. In this line, multipotent mesenchymal stromal cell-based therapeutics received special interest from the research community. Based on decades of research on cell therapy, a consensus has emerged that the therapeutic effects of cell therapy are due to the paracrine mechanisms rather than cell replacement. Exosomes, a constituent of the secretome, are nano-sized vesicles that have been a focus of intense research in recent years as a possible therapeutic agent or as a cargo to deliver drugs of interest into the central nervous system to induce neurogenesis, reduce neuroinflammation, confer neuroregeneration/neuroprotection, and improve cognitive and motor functions. In this review, we have discussed the neuroprotective properties of exosomes derived from adult mesenchymal stem cells, with a special focus on the role of exosomal miRNAs. We also reviewed various strategies to improve exosome production and their content for better therapeutic effects. Further, we discussed the utilization of ectomesenchymal stem cells like dental pulp stem cells and their exosomes in treating neurodegenerative diseases.

Keywords:  Ectomesenchymal stem cells; Exosomal miRNA; Exosome engineering; Exosome therapeutics; Neurodegeneration; Neuroprotection

DOI:  https://doi.org/10.1016/j.lfs.2024.123019
Mol Ther Nucleic Acids. 2024 Sep 10. 35(3): 102280

Emerging trends in virus and virus-like particle gene therapy delivery to the brain.

Heshadi Primrose Mandalawatta, K C Rajendra, Kirsten Fairfax, Alex W Hewitt.

  Recent advances in gene therapy and gene-editing techniques offer the very real potential for successful treatment of neurological diseases. However, drug delivery constraints continue to impede viable therapeutic interventions targeting the brain due to its anatomical complexity and highly restrictive microvasculature that is impervious to many molecules. Realizing the therapeutic potential of gene-based therapies requires robust encapsulation and safe and efficient delivery to the target cells. Although viral vectors have been widely used for targeted delivery of gene-based therapies, drawbacks such as host genome integration, prolonged expression, undesired off-target mutations, and immunogenicity have led to the development of alternative strategies. Engineered virus-like particles (eVLPs) are an emerging, promising platform that can be engineered to achieve neurotropism through pseudotyping. This review outlines strategies to improve eVLP neurotropism for therapeutic brain delivery of gene-editing agents.

Keywords:  MT: Delivery Strategies; blood-brain barrier; delivery systems; engineered virus-like particles; gene editing; neurological diseases; virus pseudotyping

DOI:  https://doi.org/10.1016/j.omtn.2024.102280
Mol Biotechnol. 2024 Sep 02.

Next-Generation Therapeutic Antibodies for Cancer Treatment: Advancements, Applications, and Challenges.

Abhavya Raja, Abhishek Kasana, Vaishali Verma.

  The field of cancer treatment has evolved significantly over the last decade with the emergence of next-generation therapeutic antibodies. Conventional treatments like chemotherapy pose significant challenges, including adverse side effects. Monoclonal antibodies have paved the way for more targeted and effective interventions. The evolution from chimeric to humanized and fully human antibodies has led to a reduction in immunogenicity and enhanced tolerance in vivo. The advent of next-generation antibodies, including bispecific antibodies, nanobodies, antibody-drug conjugates, glyco-engineered antibodies, and antibody fragments, represents a leap forward in cancer therapy. These innovations offer increased potency, adaptability, and reduced drug resistance. Challenges such as target validation, immunogenicity, and high production costs exist. However, technological advancements in antibody engineering techniques provide optimism for addressing these issues. The future promises a paradigm shift, where ongoing research will propel these powerful antibodies to the forefront, revolutionizing the fight against cancer and creating new preventive and curative treatments. This review provides an overview of three next-generation antibody-based molecules, namely bispecific antibodies, antibody-drug conjugates, and nanobodies that have shown promising results in cancer treatment. It discusses the evolution of antibodies from conventional forms to next-generation molecules, along with their applications in cancer treatment, production methods, and associated challenges. The review aims to offer researchers insights into the evolving landscape of next-generation antibody-based cancer therapeutics and their potential to revolutionize treatment strategies.

Keywords:  Antibody-drug conjugates; Bispecific antibodies; Cancer; Nanobodies; Therapeutics

DOI:  https://doi.org/10.1007/s12033-024-01270-y
Adv Healthc Mater. 2024 Sep 06. e2401906

Organelle Specific Macrophage Engineered Vesicles Differentially Reprogram Macrophage Polarization.

Khaga R Neupane, Surya P Aryal, Brock T Harvey, Geraldine San Ramon, Byeong Chun, J Robert McCorkle, Jill M Kolesar, Peter M Kekenes-Huskey, Christopher I Richards.

  Tumor-associated macrophages (TAMs) represent the majority of the immune cells present in the tumor microenvironment. These macrophages exhibit an anti-inflammatory (M2)-like physiological state and execute immune-suppressive and tumor-supporting properties. With TAMs being plastic, there is a growing interest in reprogramming them toward a pro-inflammatory (M1)-like phenotype that exhibits anti-tumoral properties. Recent studies have demonstrated that both engineered vesicles derived from macrophages and endogenous extracellular vesicles produced by macrophages can be programmed to alter macrophage phenotype. Here it is demonstrated that pro-inflammatory macrophage-engineered subcellular vesicles (MEVs) have differential properties based on their organelle of origin. Endoplasmic reticulum specific MEVs (erMEVs) treated M2 macrophages exhibit enhanced pro-inflammatory cytokine production compared to plasma membrane specific MEVs (pmMEVs) treated M2 macrophages. In addition, under in vitro co-culture conditions, erMEVs elicit superior efficacy in suppressing the viability of cancer cells compared to the same concentration of pmMEVs. Furthermore, erMEVs and pmMEVs maintain differences in their membrane proteins, that regulate the repolarization efficacy of M2 macrophages toward an M1-like phenotype. In addition, The M2 to M1 repolarizing efficacy of MEVs can be altered by changing the activity of the membrane proteins present on erMEVs or pmMEVs.

Keywords:  cancer; exosome; immunomodulation; macrophages; vesicles

DOI:  https://doi.org/10.1002/adhm.202401906
Biomaterials. 2024 Aug 20. pii: S0142-9612(24)00287-4. [Epub ahead of print]313 122753

Ligand-free biodegradable poly(beta-amino ester) nanoparticles for targeted systemic delivery of mRNA to the lungs.

Erin W Kavanagh, Stephany Y Tzeng, Neeraj Sharma, Garry R Cutting, Jordan J Green.

  Non-viral nanoparticles (NPs) have seen heightened interest as a delivery method for a variety of clinically relevant nucleic acid cargoes in recent years. While much of the focus has been on lipid NPs, non-lipid NPs, including polymeric NPs, have the possibility of improved efficacy, safety, and targeting, especially to non-liver organs following systemic administration. A safe and effective systemic approach for intracellular delivery to the lungs could overcome limitations to intratracheal/intranasal delivery of NPs and improve clinical benefit for a range of diseases including cystic fibrosis. Here, engineered biodegradable poly (beta-amino ester) (PBAE) NPs are shown to facilitate efficient delivery of mRNA to primary human airway epithelial cells from both healthy donors and individuals with cystic fibrosis. Optimized NP formulations made with differentially endcapped PBAEs and systemically administered in vivo lead to high expression of mRNA within the lungs in BALB/c and C57 B/L mice without requiring a complex targeting ligand. High levels of mRNA-based gene editing were achieved in an Ai9 mouse model across bronchial, epithelial, and endothelial cell populations. No toxicity was observed either acutely or over time, including after multiple systemic administrations of the NPs. The non-lipid biodegradable PBAE NPs demonstrate high levels of transfection in both primary human airway epithelial cells and in vivo editing of lung cell types that are targets for numerous life-limiting diseases particularly single gene disorders such as cystic fibrosis and surfactant deficiencies.

Keywords:  Cystic fibrosis; Gene delivery; Nanoparticle; Poly(beta-amino ester); Targeting; mRNA

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122753
Acta Biomater. 2024 Sep 03. pii: S1742-7061(24)00505-1. [Epub ahead of print]

Lipopolymer/siRNA Complexes Engineered for Optimal Molecular and Functional Response with Chemotherapy in FLT3-Mutated Acute Myeloid Leukemia.

Aysha S Ansari, Cezary Kucharski, Remant Kc, Daniel Nisakar, Ramea Rahim, Xiaoyan Jiang, Joseph Brandwein, Hasan Uludağ.

  Approximately 25% of newly diagnosed AML patients display an internal tandem duplication (ITD) in the fms-like tyrosine kinase 3 (FLT3) gene. Although both multi-targeted and FLT3 specific tyrosine kinase inhibitors (TKIs) are being utilized for clinical therapy, drug resistance, short remission periods, and high relapse rates are challenges that still need to be tackled. RNA interference (RNAi), mediated by short interfering RNA (siRNA), presents a mechanistically distinct therapeutic platform with the potential of personalization due to its gene sequence-driven mechanism of action. This study explored the use of a non-viral approach for delivery of FLT3 siRNA (siFLT3) in FLT3-ITD positive AML cell lines and primary cells as well as the feasibility of combining this treatment with drugs currently used in the clinic. Treatment of AML cell lines with FLT3 siRNA nanocomplexes resulted in prominent reduction in cell proliferation rates and induction of apoptosis. Quantitative analysis of relative mRNA transcript levels revealed downregulation of the FLT3 gene, which was accompanied by a similar decline in FLT3 protein levels. Moreover, an impact on leukemic stem cells was observed in a small pool of primary AML samples through significantly reduced colony numbers. An absence of a molecular response post-treatment with lipopolymer/siFLT3 complexes in peripheral blood mononuclear cells, obtained from healthy individuals, denoted a passive selectivity of the complexes towards malignant cells. The effect of combining lipopolymer/siFLT3 complexes with daunorubucin and FLT3 targeting TKI gilteritinib led to a significant augmentation of anti-leukemic activity. These findings demonstrate the promising potential of RNAi implemented with lipopolymer complexes for AML molecular therapy. The study prospectively supports the addition of RNAi therapy to current treatment modalities available to target the heterogeneity prevalent in AML. STATEMENT OF SIGNIFICANCE: We show that a clinically validated target, the FLT3 gene, can be eradicated in leukemia cells using non-viral RNAi. We validated these lipopolymers as effective vehicles to deliver nucleic acids to leukemic cells. The potency of the lipopolymers was superior to that of the 'gold-standard' delivery agent, lipid nanoparticles (LNPs), which are not effective in leukemia cells at clinically relevant doses. Mechanistic studies were undertaken to probe structure-function relationships for effective biomaterial formulations. Cellular and molecular responses to siRNA treatment have been characterized in cell models, including leukemia patient-derived cells. The use of the siRNA therapy with clinically used chemotherapy was demonstrated.

Keywords:  Leukemia therapy; Nanoparticles; acute myeloid leulemia; lipopolymers; patient samples; siRNA

DOI:  https://doi.org/10.1016/j.actbio.2024.08.053
J Microbiol Biotechnol. 2024 Aug 19. 34(10): 1-12

Synthetic Biology-Driven Microbial Therapeutics for Disease Treatment.

Tae Hyun Kim, Byung Kwan Cho, Dae-Hee Lee.

  The human microbiome, consisting of microorganisms that coexist symbiotically with the body, impacts health from birth. Alterations in gut microbiota driven by factors such as diet and medication can contribute to diseases beyond the gut. Synthetic biology has paved the way for engineered microbial therapeutics, presenting promising treatments for a variety of conditions. Using genetically encoded biosensors and dynamic regulatory tools, engineered microbes can produce and deliver therapeutic agents, detect biomarkers, and manage diseases. This review organizes engineered microbial therapeutics by disease type, emphasizing innovative strategies and recent advancements. The scope of diseases includes gastrointestinal disorders, cancers, metabolic diseases, infections, and other ailments. Synthetic biology facilitates precise targeting and regulation, improving the efficacy and safety of these therapies. With promising results in animal models, engineered microbial therapeutics provide a novel alternative to traditional treatments, heralding a transformative era in diagnostics and treatment for numerous diseases.

Keywords:  Engineered microbial therapeutics; GI disease; metabolic disease infection; synthetic biology; tumor

DOI:  https://doi.org/10.4014/jmb.2407.07004
J Mater Chem B. 2024 Sep 03.

Nanomaterial combined engineered bacteria for intelligent tumor immunotherapy.

Shurong Qin, Guanzhong He, Jingjing Yang.

Cancer remains the leading cause of human death worldwide. Compared to traditional therapies, tumor immunotherapy has received a lot of attention and research focus due to its potential to activate both innate and adaptive immunity, low toxicity to normal tissue, and long-term immune activity. However, its clinical effectiveness and large-scale application are limited due to the immunosuppression microenvironment, lack of spatiotemporal control, expensive cost, and long manufacturing time. Recently, nanomaterial combined engineered bacteria have emerged as a promising solution to the challenges of tumor immunotherapy, which offers spatiotemporal control, reversal of immunosuppression, and scalable production. Therefore, we summarize the latest research on nanomaterial-assisted engineered bacteria for precise tumor immunotherapies, including the cross-talk of nanomaterials and bacteria as well as their application in different immunotherapies. In addition, we further discuss the advantages and challenges of nanomaterial-engineered bacteria and their future prospects, inspiring more novel and intelligent tumor immunotherapy.

DOI: https://doi.org/10.1039/d4tb00741g
Small. 2024 Sep 05. e2404463

Gene-Engineered Cerium-Exosomes Mediate Atherosclerosis Therapy Through Remodeling of the Inflammatory Microenvironment and DNA Damage Repair.

Peng Wei, Yifan Wang, Haiyan Feng, Fan Zhang, Zhenyan Ji, Kai Zhang, Qiang Zhang, Lixian Jiang, Yuxuan Qian, Yimu Fu.

  The pro-inflammatory immune microenvironment in the localized lesion areas and the absence of DNA damage repair mechanisms in endothelial cells serve as essential accelerating factors in the development of atherosclerosis. The lack of targeted therapeutic strategies represents a significant limitation in the efficacy of therapeutic agents for atherosclerosis. In this study, Genetically engineered SNHG12-loaded cerium-macrophage exosomes (Ce-Exo) are designed as atherosclerosis-targeting agents. In vivo studies demonstrated that Ce-Exo exhibited multivalent targeting properties for macrophages, with a 4.1-fold higher atherosclerotic plaque-aggregation ability than that of the control drugs. This suggests that Ce-Exo has a higher homing capacity and deeper penetration into the atherosclerotic plaque. In apolipoprotein E-deficient mice, Ce-Exo found to effectively remodel the immune microenvironment in the lesion area, repair endothelial cell damage, and inhibit the development of atherosclerosis. This study provides a novel approach to the treatment of atherosclerosis and demonstrates the potential of cell-derived drug carriers in biomedicine.

Keywords:  DNA damage repair; atherosclerosis; biomimetic; gene‐engineered cerium‐exosomes; inflammatory microenvironment remodeling

DOI:  https://doi.org/10.1002/smll.202404463
J Am Chem Soc. 2024 Aug 31.

RNA-Activatable Near-Infrared Photosensitizer for Cancer Therapy.

Yin Jiang, Shumei Huang, Haiying Ma, Jintao Weng, Xiaomeng Du, Zhenxin Lin, Jaewon Kim, Wenhui You, Huatang Zhang, Dongqing Wang, Jong Seung Kim, Hongyan Sun.

Photodynamic therapy (PDT) has recently come to the forefront as an exceptionally powerful and promising method for the treatment of cancer. Existing photosensitizers are predominantly engineered to target diverse biomolecules, including proteins, DNA, lipids, and carbohydrates, and have proven to greatly enhance the efficacy or specificity of PDT. However, it is noteworthy that there exists a conspicuous scarcity of photosensitizers specifically designed to target RNAs. Recognizing the crucial and multifaceted roles played by RNAs in various cellular processes and disease states, we have ventured into the development of a novel RNA-targeting photosensitizer, named Se-718, designed specifically for PDT-based cancer therapy. Se-718 has been engineered to exhibit a high molar absorption coefficient in the NIR region, which is crucial for effective PDT. More importantly, Se-718 has demonstrated a distinct RNA-targeting capability, as evidenced through rigorous testing in both circular dichroism and fluorescence experiments. Furthermore, Se-718 has been shown to display both type I and type II photodynamic properties. This unique characteristic enables the efficient killing of cancer cells under a wide range of oxygen conditions, both normoxic (21% O2) and hypoxic (2% O2). The IC50 of Se-718 can be as low as 100 nM, and its light-to-dark toxicity ratio is an impressive 215 times higher, outperforming most photosensitizers currently available. Moreover, in vivo studies conducted with tumor-bearing mice have demonstrated the excellent antitumor effects and high safety profile of Se-718. Considering the outstanding PDT efficacy of Se-718, we are optimistic that the development of RNA-targeting photosensitizers may provide an innovative and highly effective option for cancer therapeutics in the near future.

DOI: https://doi.org/10.1021/jacs.4c09470
Hum Gene Ther. 2024 Aug 30.

Unconstrained precision mitochondrial genome editing with αDdCBEs.

Santiago R Castillo, Brandon W Simone, Karl J Clark, Patricia Devaux, Stephen C Ekker.

DddA-derived cytosine base editors (DdCBEs) enable the targeted introduction of C•G-to-T•A conversions in mitochondrial DNA (mtDNA). DdCBEs work in pairs, with each arm composed of a transcription activator-like effector (TALE), a split double-stranded DNA deaminase half, and a uracil glycosylase inhibitor. This pioneering technology has helped improve our understanding of cellular processes involving mtDNA and has paved the way for the development of models and therapies for genetic disorders caused by pathogenic mtDNA variants. Nonetheless, given the intrinsic properties of TALE proteins, several target sites in human mtDNA are predicted to remain out of reach to DdCBEs and other TALE-based technologies. Specifically, due to the conventional requirement for a thymine immediately upstream of the TALE target sequences (i.e., the 5'-T constraint), over 150 loci in the human mitochondrial genome are presumed to be inaccessible to DdCBEs. Previous attempts at circumventing this requirement, either by developing monomeric DdCBEs or utilizing DNA-binding domains alternative to TALEs, have resulted in suboptimal specificity profiles with reduced therapeutic potential. Here, aiming to challenge and elucidate the relevance of the 5'-T constraint in the context of DdCBE-mediated mtDNA editing, and to expand the range of motifs that are editable by this technology, we generated DdCBEs containing TALE proteins engineered to recognize all 5' bases. These modified DdCBEs are herein referred to as αDdCBEs. Notably, 5'-T-noncompliant canonical DdCBEs efficiently edited mtDNA at diverse loci. However, they were frequently outperformed by αDdCBEs, which exhibited significant improvements in activity and specificity, regardless of the most 5' bases of their TALE binding sites. Furthermore, we showed that αDdCBEs are compatible with the enhanced DddAtox variants DddA6 and DddA11, and we validated TALE shifting with αDdCBEs as an effective approach to optimize base editing outcomes. Overall, αDdCBEs enable efficient, specific, and unconstrained mitochondrial base editing.

DOI: https://doi.org/10.1089/hum.2024.073
JACS Au. 2024 Aug 26. 4(8): 2957-2965

Overexpression of a Designed Mutant Oxyanion Binding Protein ModA/WtpA in Acidithiobacillus ferrooxidans for the Low pH Recovery of Molybdenum and Rhenium.

Heejung Jung, Virginia Jiang, Zihang Su, Yuta Inaba, Farid F Khoury, Scott Banta.

Molybdenum and rhenium are critically important metals for a number of emerging technologies. We identified and characterized a molybdenum/tungsten transport protein (ModA/WtpA) of Acidithiobacillus ferrooxidans and demonstrated the binding of tungstate, molybdate, and chromate. We used computational design to expand the binding capabilities of the protein to include perrhenate. A disulfide bond was engineered into the binding pocket of ModA/WtpA to introduce a more favorable geometric coordination and surface charge distribution for oxyanion binding. The mutant protein experimentally demonstrated a 2-fold higher binding affinity for molybdate and 6-fold higher affinity for perrhenate. The overexpression of the wild-type and mutant ModA/WtpA proteins in A. ferrooxidans cells enhanced the innate tungstate, molybdate, and chromate binding capacities of the cells to up to 2-fold higher. In addition, the engineered cells expressing the mutant protein exhibited enhanced perrhenate binding, showing 5-fold and 2-fold higher binding capacities compared to the wild-type and ModA/WtpA-overexpressing cells, respectively. Furthermore, the engineered cell lines enhanced biocorrosion of stainless steel as well as the recovered valuable metals from an acidic wastewater generated from molybdenite processing. The improved binding efficiency for the oxyanion metals, along with the high selectivity over nontargeted metals under mixed metal environments, highlights the potential value of the engineered strains for practical microbial metal reclamation under low pH conditions.

DOI: https://doi.org/10.1021/jacsau.4c00296