bims-engexo 2026-10-04 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–10–04
ten papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Understanding the Potential of Antibody-Drug Conjugates Functionalized Engineered Exosomes in Hepatocellular Carcinoma Therapy: A Comprehensive Narrative Review.
Extracellular vesicles: rising stars among drug delivery systems?
Bone-Targeted Engineered Exosomes Delivering Betaine Alleviate Osteoporosis via Autophagy-Driven Osteogenesis.
Anti-CD19-engineered exosomes enable B cell-targeted anti-BAFF mRNA delivery to alleviate lupus progression.
Targeted Delivery of NGF-Pretreated Schwann Cell-Derived Exosomes for Osteoporosis Therapy: Overcoming Pain while Enhancing Bone Formation.
OX40 ligand-engineered dendritic cell nanovesicles potentiate antitumor immunity through dual-mode T cell activation.
Hybrid-Fused Extracellular Vesicles from M2 Macrophages and Keratinocytes Attenuate Ultraviolet B-Induced Skin Photoaging via the Interleukin-4 Receptor Alpha/Janus Kinase/Signal Transducer and Activator of Transcription 3-Mediated Pathway.
Engineered CAR-T extracellular vesicles loaded with miR-17-5p inhibitor suppress hepatocellular carcinoma progression.
The application of engineered exosome-mimetic lipid nanoparticles in the hepatic rejuvenation of aged donor livers.
Split-Type Microneedles Loaded with miR-125b-Enriched Extracellular Vesicles: A Sustained Preventive and Therapeutic Platform for Nitrogen Mustard-Induced Skin Injuries.

Health Sci Rep. 2026 Oct;9(10): e73289

Understanding the Potential of Antibody-Drug Conjugates Functionalized Engineered Exosomes in Hepatocellular Carcinoma Therapy: A Comprehensive Narrative Review.

Subham Sarkar, Avinaba Bose, Jenifer Rajak, Arup Kumar Mitra, Ajoy Kumer, Bikram Dhara.

   Background: Exosomes are naturally secreted nanovesicles with high biocompatibility, low immunogenicity, and the ability to traverse biological barriers, making them attractive theragnostic carriers. When engineered to present tumor-specific antibodies and to deliver antibody-drug conjugates (ADCs), they may enhance selective targeting of hepatocellular carcinoma (HCC).
Methods: This narrative review synthesizes the multidisciplinary field of exosome bioengineering, ADCs, and HCC diagnosis and therapy, covering topics from click chemistry to translational challenges. A comprehensive search of PubMed, Web of Science, and Scopus (1991-2026) identified relevant studies on exosome-based targeted delivery, and diagnosis and therapeutics in HCC. Included studies focused on engineered exosomes, ADCs, and tumor-specific targeting, with rigorous characterization and relevance to HCC diagnosis and therapy. The review aims to provide a conceptual synthesis, highlighting translational progress and future directions in engineered exosome-based cancer diagnosis and therapy.
Results: The exosomal lipid bilayer protects encapsulated therapeutic cargo from premature degradation in circulation, while antibody display confers high-affinity recognition of HCC cells. A dual-targeting paradigm leveraging both the exosome's inherent tropism and antibody specificity supports increased intra-tumoral delivery and reduced off-target exposure relative to conventional modalities. Co-loading of imaging probes can enable integrated theragnostics, facilitating visualization of biodistribution, target engagement, and treatment response. However, as clinical data remains limited, these anticipated advantages in the human therapy should be established by thorough experimentation and clinical trials.
Conclusion: ADC-functionalized exosomes (immuno-exosomes) can offer a suitable platform for precise HCC targeting with the potential to improve therapeutic index and enable real-time response monitoring. Translational progress will depend on robust, scalable manufacturing, rigorous characterization of purity and potency, and comprehensive evaluation of safety, pharmacokinetics, and efficacy in preclinical models and clinical studies.

Keywords:  antibody‐drug conjugate; diagnosis; exosomes; hepatocellular carcinoma; targeted delivery; therapy

DOI:  https://doi.org/10.1002/hsr2.73289
J Control Release. 2026 Oct 02. pii: S0168-3659(26)00836-9. [Epub ahead of print] 115432

Extracellular vesicles: rising stars among drug delivery systems?

Volkmar Weissig.

  Engineered extracellular vesicles (EVs) are increasingly being lauded as the next generation of drug delivery systems. Their intrinsic biological properties as well as their ability to transport therapeutic drug molecules have generated enormous enthusiasm. In this opinion paper, the author recaps that many of the properties now presented as unique advantages of engineered EVs, including biocompatibility, low toxicity, cargo-loading capacity, and surface functionalization, have long been established features of synthetic lipid vesicles. However, the major obstacles that have limited clinical translation of multifunctional liposomes, particularly targeted liposomes, are also likely to pose substantial challenges for engineered targeted EVs. Rather than viewing engineered EVs as a revolutionary new class of nanocarriers, the author proposes that their development should be guided by the successes and limitations of liposome technology. Studying the lessons learned from liposome technology may help prevent repeating historical mistakes and facilitate the rational development of clinically translatable EV-based therapeutics.

Keywords:  Drug delivery; Drug targeting; Extracellular vesicles; Liposomes

DOI:  https://doi.org/10.1016/j.jconrel.2026.115432
Adv Mater. 2026 Sep 27. e75185

Bone-Targeted Engineered Exosomes Delivering Betaine Alleviate Osteoporosis via Autophagy-Driven Osteogenesis.

Xiaorong Li, Mengsha Li, Zhenghao Li, Jiaying Gu, Linzhen Mo, Yuetong Zhu, Yang Chen, Leli Zeng, Yihang Pan, Chao Zhang, Yunhui Si.

  Dysregulated bone remodeling, attenuated endogenous osteogenic capacity, and the lack of bone-targeting capability in therapeutics constitute the core challenges in current clinical interventions for osteoporosis. In this study, a hybrid nanodelivery system integrating betaine-loaded metal-organic frameworks with engineered exosomes (BZ@Exos) is constructed to restore bone metabolic homeostasis and improve bone microstructure. The engineered exosomes co-overexpressing CXCR4 and CD47 proteins on the surface exhibit high bone tissue targeting efficiency and evade clearance by the mononuclear phagocyte system, while ZIF-8 enables stable encapsulation of betaine. Internalized betaine promotes nuclear translocation of TFEB via targeted binding to the 14-3-3 protein, enhances autophagic flux in senescent bone marrow mesenchymal stem cells (BMSCs), and thereby facilitates their osteogenic differentiation. In parallel, BZ@Exos significantly inhibits osteoclast-mediated bone resorption and restores bone metabolic homeostasis. In vivo assays demonstrate that intravenously administered BZ@Exos successfully reverses bone loss and alleviates senescence-related phenotypes in ovariectomized rat models of osteoporosis. This novel therapeutic system with integrated functions of bone homeostasis remodeling, regenerative potential restoration, and precise targeting provides a new perspective for osteoporosis treatment.

Keywords:  autophagy; betaine; bone‐targeting; engineered exosomes; osteoporosis

DOI:  https://doi.org/10.1002/adma.75185
Mol Ther. 2026 Sep 29. pii: S1525-0016(26)00763-X. [Epub ahead of print]

Anti-CD19-engineered exosomes enable B cell-targeted anti-BAFF mRNA delivery to alleviate lupus progression.

Linda Zeng, Jingxian Shu, Shuping Zhong, Xin Dong, Yongjian Wu, Xi Huang.

DOI: https://doi.org/10.1016/j.ymthe.2026.08.040
ACS Biomater Sci Eng. 2026 Sep 28.

Targeted Delivery of NGF-Pretreated Schwann Cell-Derived Exosomes for Osteoporosis Therapy: Overcoming Pain while Enhancing Bone Formation.

Yinnan Guo, Sha Cui, Wenting Zhang, Yali Wu, Qi Song, Le Chang, Xiangying Jiao.

  Osteoporosis (OP) is a prevalent skeletal disorder characterized by decreased bone mass and increased fragility, leading to fractures and chronic pain. Nerve growth factor (NGF) plays a pivotal role in bone homeostasis and neuro-regeneration but paradoxically exacerbates pain. This study investigated the therapeutic potential of engineered, bone-targeting exosomes derived from NGF-pretreated Schwann cells (NGF-Exo-Pep) for the treatment of OP. We demonstrated that NGF-Exo-Pep effectively promoted osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells (BMSCs) in vitro, while also enhancing Schwann cell proliferation, migration, and neurotrophic factor secretion. Mechanistically, miRNA sequencing revealed that NGF-Exo-Pep was enriched in osteogenic miRNAs. In vivo, NGF-Exo-Pep treatment in ovariectomized mice significantly improved bone microarchitecture, increased osteoblast activity, reduced osteoclast activity, and neurotization of bone tissue. Notably, NGF-Exo-Pep alleviated pain-related behaviors by downregulating pain mediators and reducing c-Fos expression in the spinal cord. This study presented a novel and promising strategy for OP treatment, harnessing the pro-regenerative properties of NGF while mitigating its pain-inducing side effects.

Keywords:  nerve growth factor; neurotization; osteogenesis; osteoporosis; pain

DOI:  https://doi.org/10.1021/acsbiomaterials.6c00906
J Control Release. 2026 Sep 30. pii: S0168-3659(26)00827-8. [Epub ahead of print] 115423

OX40 ligand-engineered dendritic cell nanovesicles potentiate antitumor immunity through dual-mode T cell activation.

Zhongqian Yang, Yiting Ding, Ying Yang, Chuyuan Deng, Xin Yin, Tong Yu, Jonathan Ma, Qiong Long, Yanbing Ma.

  The efficacy of classical dendritic cell (DC)-based cancer vaccines is limited by poor in vivo stability, inefficient lymph node delivery, and the immunosuppressive tumor microenvironment. Here, we developed a nanovaccine platform by engineering DC-derived nanovesicles (NVs) and established a membrane-anchoring strategy based on a recombinant cytolysin A (ClyA) fusion protein that efficiently inserts OX40 ligand (OX40L) from the extracellular side onto the surface of mature DCs and their derived NVs. The resulting E7-OX40L-NV, loaded with HPV16 E7 peptide, retained native and modified DC membrane proteins, exhibited efficient migration to draining lymph nodes, and showed good biocompatibility. In vitro, E7-OX40L-NV directly activated both naive and antigen-experienced antigen-specific CD8+ T cells and induced cytotoxic function. After uptake by DCs, the vesicles transferred peptide-MHC (pMHC) and OX40L to the DC surface, indirectly enhancing CD8+ T cell responses. In therapeutic TC-1 tumor models, E7-OX40L-NV induced potent antitumor immunity, including enhanced T cell effector function, reduced regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), increased intratumoral infiltration of functional T cells, remodeled T cell proliferation and exhaustion dynamics, and increased formation of long-lived memory precursor effector cells (MPECs), leading to significant tumor suppression and complete regression in a proportion of mice that rejected contralateral tumor rechallenge. Co-delivery of OX40L and antigen on the same NV was more effective than a physical mixture, underscoring the importance of spatial coordination. This ClyA-mediated membrane functionalization strategy provides a versatile tool for engineering cell-derived vesicles, and OX40L-engineered DC nanovesicles offer a promising platform for developing next-generation personalized cancer vaccines.

Keywords:  Antitumor immunity; Dendritic cells; Nanovesicles; OX40 ligand; T cell activation

DOI:  https://doi.org/10.1016/j.jconrel.2026.115423
ACS Appl Mater Interfaces. 2026 Oct 01.

Hybrid-Fused Extracellular Vesicles from M2 Macrophages and Keratinocytes Attenuate Ultraviolet B-Induced Skin Photoaging via the Interleukin-4 Receptor Alpha/Janus Kinase/Signal Transducer and Activator of Transcription 3-Mediated Pathway.

Yangyang Hao, Yunjia Shen, Xi Chen, Mengwei Chou, Jianqiang Yang.

  Chronic ultraviolet B (UVB) irradiation represents a primary environmental trigger of skin photoaging, a process defined by disrupted cutaneous redox balance, sustained low-grade inflammation, progressive cellular senescence, and impaired dermal collagen homeostasis. Among the underlying pathogenic events, aberrant macrophage polarization, progressive dermal cell senescence, and persistent collagen breakdown act as central drivers of photoaging deterioration. Traditional extracellular vesicles (EVs) derived from a single cell source carry a restricted repertoire of bioactive cargos, and thus fail to concurrently address the multiple interconnected pathological pathways that characterize photoaged skin. In this work, we generated hybrid fused extracellular vesicles (M2-KC-fEV) by combining vesicles from M2 macrophages and epidermal keratinocytes, and systematically assessed their protective efficacy against UVB-induced skin photodamage along with the underlying molecular regulatory mechanisms. Multidimensional characterization verified that M2-KC-fEV displayed a homogeneous size distribution, typical bilayer vesicular morphology, and stable surface zeta potential, and were readily internalized by skin derived cells. In UVB-injured mouse keratinocytes and dermal fibroblasts, treatment with M2-KC-fEV markedly reduced DNA double-strand breaks, suppressed excess reactive oxygen species production, and lowered proinflammatory cytokine secretion. The vesicles also alleviated cellular senescence and restored the proliferative and migratory abilities of damaged skin cells. In addition, the hybrid vesicle preparation modulated macrophage polarization states, inhibiting the proinflammatory M1 phenotype while shifting cells toward the anti-inflammatory, tissue reparative M2 phenotype. In line with in vitro observations, prophylactic subcutaneous administration of M2-KC-fEV in UVB-challenged SKH-1 hairless mice visibly reduced skin wrinkling and roughness, normalized epidermal thickness, enhanced type I collagen deposition, and inhibited MMP-3-driven collagen degradation. Mechanistic analyses revealed that the polarization-regulating effect of M2-KC-fEV is associated with the IL-4Rα/JAK/STAT3 signaling axis. Activation of this axis contributes to dampening inflammatory cascade amplification, alleviating oxidative damage and senescence accumulation, and ultimately ameliorating UVB-induced cutaneous photoaging. Collectively, M2-KC-fEV integrate anti-inflammatory, epidermal-protective, and dermal matrix-modulating activities, delivering enhanced combinatorial benefits against UVB-induced skin injury. Our findings support the potential of this cell-free nanotherapeutic platform for the prevention and mitigation of skin photoaging.

Keywords:  IL-4Rα/JAK/STAT3 signaling pathway; M2-KC-fEV; macrophage polarization; nanotherapeutic strategy; skin photoaging

DOI:  https://doi.org/10.1021/acsami.6c09469
Front Immunol. 2026 ;17 1919449

Engineered CAR-T extracellular vesicles loaded with miR-17-5p inhibitor suppress hepatocellular carcinoma progression.

Zhifeng Zhou, Huiling Wu, Shen Zhao, Mingshui Chen, Wansong Lin, Jieyu Li, Qingfeng Zheng.

   Background: Hepatocellular carcinoma (HCC) immune escape is co-driven by tumor malignant proliferation and an immunosuppressive tumor microenvironment, characterized by frequently impaired natural killer (NK) cell function. Previous research indicated that HCC cell-secreted extracellular vesicles (EVs) deliver miR-17-5p, inhibiting the RUNX1 pathway and downregulating the activating receptor NKG2D in NK cells, which ultimately results in NK cell dysfunction. Although chimeric antigen receptor (CAR)-T therapy has achieved remarkable efficacy in hematological malignancies, it encounters significant challenges in treating solid tumors, including HCC. Recent studies have confirmed that CAR-T cell-derived EVs (CAR-T EVs) retain CAR targeting specificity and carry cytotoxic effectors such as granzyme B and perforin, demonstrating independent antitumor potential.
Objective: This study aimed to develop engineered CAR-T EVs loaded with a miR-17-5p inhibitor (EV-miR inhibitor) and evaluate their combined therapeutic efficacy against HCC through direct tumor cytotoxicity and restoration of NK cell function.
Methods: This study constructed NKG2D-targeted third-generation CAR-T cells, isolated CAR-T EVs via ultracentrifugation, characterized EV properties using multiple assays, and generated engineered CAR-T EVs loaded with a miR-17-5p inhibitor (EV-miR inhibitor). The therapeutic effects of this system against HCC were verified both in vitro and in a zebrafish HCC xenograft model.
Results: CAR-T EVs exhibited characteristic cup-shaped morphology and robust expression of canonical EV markers together with the engineered NKG2D extracellular domain. Results indicated that CAR-T EVs entered HCC cells and exhibited concentration-dependent cytotoxicity against HCC cells without affecting the viability of normal hepatocytes. The loading of the miR-17-5p inhibitor was efficient, and the procedure did not alter the morphology, particle size, or marker expression of CAR-T EVs. EV-miR inhibitor effectively restored NKG2D and RUNX1 expression in miR-17-5p-overexpressing NK cells, significantly enhancing NK cell cytotoxicity against HCC and promoting IFN-γ secretion in vitro. In vivo experiments further confirmed that EV-miR inhibitor treatment markedly enhanced the antitumor activity of NK cells, leading to significant tumor growth inhibition in zebrafish xenografts.
Conclusions: In conclusion, this study demonstrates that NKG2D-targeted CAR-T EVs exert combined anti-HCC activities through direct tumor cytotoxicity and restoration of NK cell function, providing a novel immunotherapeutic strategy for HCC.

Keywords:  CAR-T cell-derived extracellular vesicles; hepatocellular carcinoma (HCC); miR-17-5p inhibitor; natural killer (NK) cells; zebrafish xenografts

DOI:  https://doi.org/10.3389/fimmu.2026.1919449
Biomater Adv. 2026 Sep 24. pii: S2772-9508(26)00496-6. [Epub ahead of print]191 215196

The application of engineered exosome-mimetic lipid nanoparticles in the hepatic rejuvenation of aged donor livers.

Lianghao Zhang, Ruidong Ding, Dongpei Zheng, Yingying Liu, Zhanbo Sun, Mei Liu, Shunjie Wu, Guojie Liu, Bingni Li, Zhiwen Zhao, Kun Yu, Xinwei Li, Feng Wang, Chuanshen Xu.

  The severe global shortage of donor organs necessitates the utilization of aged extended-criteria donor (ECD) livers, which are susceptible to ischemic injury and exhibit a sluggish regeneration due to hepatic senescence. While mesenchymal stem cell-derived exosomes show regenerative promise, clinical translation is hindered by manufacturing bottlenecks and batch heterogeneity. In this study, we have developed a highly controllable, microfluidic-engineered exosome-mimetic lipid nanotherapeutic (LMP) to rejuvenate aged livers. The proposed procedure employs a "decoding and synthetic reconstruction" paradigm, where the regenerative cargo of natural exosomes is converted to a standardized 10-component core, comprising three master-regulatory miRNAs and seven functional proteins. In vitro and in vivo evaluations have demonstrated that the LMP exhibits the requisite biosafety, rapid hepatic internalization, and immunological inertness. A systemic administration of LMP effectively revitalizes baseline liver function in aged mice. In terms of mechanism, the multidimensional rejuvenation is driven by a modulating of the collapsed mitochondrial energy networks, attenuating the senescence-associated secretory phenotype (SASP), and reducing age-related fibrotic architectures. The LMP actively remodels the hepatic immune microenvironment by promoting a shift in the relative distribution of macrophage populations toward a pro-resolving M2-like phenotype, significantly attenuating chronic inflammaging. This study presents a highly scalable, multi-pathway nanomedicine that can successfully reset the hepatic senescent network, providing a promising preclinical pharmacological strategy that warrants future testing in rigorous donor-graft and transplantation settings to fully evaluate its clinical translational potential.

Keywords:  Exosome-mimetic nanotherapeutics; Hepatic rejuvenation; Liver transplantation; Macrophage polarization; Senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.1016/j.bioadv.2026.215196
ACS Appl Mater Interfaces. 2026 Sep 29.

Split-Type Microneedles Loaded with miR-125b-Enriched Extracellular Vesicles: A Sustained Preventive and Therapeutic Platform for Nitrogen Mustard-Induced Skin Injuries.

Weiqian Jiang, Qinghe Meng, Ketong Liu, Ang Li, Chaoying Jin, Bing Zhu, Ji Zhu, Minliang Wu, Qingqiang Xu, Chunyu Xue.

  Nitrogen mustard (NM) induces severe, refractory skin injuries lacking specific available therapeutics. Considering that extracellular vesicles (EVs) show promising effects in wound healing, we developed a split-type microneedle (MN-EVs@miR) loaded with miR-125b-enriched engineered EVs (EVs@miR) to treat NM-induced skin injury. EVs were isolated from human umbilical cord mesenchymal stem cells (hUMSCs), loaded with miR-125b via transfection, and then conjugated to hyaluronic acid methacryloyl (HAMA) hydrogel using acrylic acid-polyethylene glycol-N-hydroxysuccinimide (AC-PEG-NHS) to prepare microneedle tips, with polyvinyl alcohol (PVA) and sodium thiosulfate constituting the substrate. The prepared MN-EVs@miR exhibited sufficient mechanical strength (0.34 N/needle), sustained EVs@miR release over 21 days, and long-term in vivo retention (>21 days) with excellent biocompatibility. In vitro, EVs@miR enhanced cell viability, inhibited apoptosis, regulated inflammation (downregulating TNF-α, IL-1β, and IL-6; upregulating IL-10), and promoted angiogenesis. In vivo, MN-EVs@miR significantly mitigated NM-induced skin blistering and necrosis, with superior wound healing efficacy compared to that of EVs@miR injection and blank MNs. In conclusion, the split-type MN-EVs@miR provides a promising preventive and therapeutic strategy for NM-induced skin injuries with potential battlefield and clinical applications.

Keywords:  extracellular vesicles; microRNA-125b; microneedle; nitrogen mustard; skin injury

DOI:  https://doi.org/10.1021/acsami.6c12383