Lingyan Yang

The intestine plays a crucial role in regulating metabolism and immunity, with functional decline occurring during injury and ageing. Stimulating the neogenesis of intestinal stem cells (ISCs) by activating the WNT/β‐catenin signalling pathway represents a promising approach for intestinal tissue regeneration and injury repair. However, effective oral delivery of functional WNT signalling agonists to the gut remains challenging. Herein, we report a potent WNT/β‐catenin signalling‐inducing small extracellular vesicles (sEV) that can be administered orally and present remarkable therapeutic efficacy. We demonstrate that active R‐spondin1 (RSPO1) protein can be loaded onto the surface of sEV via heparan sulfate proteoglycans. Notably, sEV‐delivered RSPO1 (evRSPO1) effectively induces WNT/β‐catenin signalling‐inducing activity, enhances ISCs proliferation, and supports intestinal organoid growth in vitro. Importantly, oral administration of evRSPO1 activates the WNT/β‐catenin signalling pathway in the cryptic stem cell niche, thereby accelerating tissue repair and regeneration in a radiation‐induced intestinal injury model. Furthermore, evRSPO1 treatment induces ISCs proliferation and reverses the intestinal senescence phenotype in aged mice. Collectively, this study establishes evRSPO1 as a potential first‐in‐class, orally deliverable therapeutic that overcomes biological barriers to activate ISCs, enabling efficient intestinal tissue repair and rejuvenation.

WNT signaling is an essential pathway regulating tissue morphogenesis and regeneration. However, harnessing the pathway for regenerative medicine has been challenging due to the lack of approaches to identify and deliver specific WNT ligands to the target tissue. Herein, we reported that WNT and R-spondin (RSPO) proteins could be transported on engineered exosomes and activate the pathway synergistically. We showed that WNT3A and RSPO1 co-treatment could effectively regulate hepatic cell fate and uncovered functional crosstalk with the PPARα signaling pathway. Moreover, dual-ligand-carrying exosome (exoWNT3A/RSPO1) hyperactivated the WNT signaling and promoted efficient hepatic organoid growth compared to the small molecule inhibitor CHIR99021. Importantly, the exosome can be efficiently delivered for robust WNT signaling activation in the liver. Remarkably, exoWNT3A/RSPO1 could accelerate liver repair and regeneration under various conditions, including acute and chronic injuries and aging-associated phenotypes. Collectively, our work revealed the broad therapeutic effects of WNT signaling activation in the liver through the dual-ligand-carrying exosomes.

The rising global prevalence of Alzheimer's disease (AD) and mild cognitive impairment (MCI) underscores the urgent need to elucidate their underlying pathogenic mechanisms.

Wingless/Integrated (WNT) signaling is a central pathway governing tissue morphogenesis, stem cell maintenance, and regeneration. However, its therapeutic translation has been hindered by challenges in delivering stable and active WNT ligands over long distances to target tissues and organs. Recent advances in exosome engineering offer a new solution to this problem by delivering WNT ligands via engineered exosomes, dual-ligand vesicles to achieve robust and sustained activation of WNT signaling both in vitro and in vivo. This perspective highlights how such dual-ligand exosomes overcome the biochemical and delivery barriers of WNT activation, promote liver regeneration under diverse conditions, including acute, chronic, and aging-associated injuries, and establish a conceptual framework for next-generation regenerative therapeutics. These findings mark a pivotal step toward reprogramming tissue homeostasis and rejuvenation through bioengineered signaling vesicles.

Exosomes are membrane-bound vesicles secreted by various cell types into the extracellular environment and contain kinds of bioactive molecules. These molecules can mediate various biological processes such as cell differentiation, proliferation, and survival, making them attractive for tissue regeneration and repair. Owing to their nanoscale size, bilayer membrane structure, and receptor-mediated transcytosis, exosomes can cross the blood-brain barrier (BBB) and reach the central nervous system (CNS) tissue. Additionally, exosomes can be loaded with exogenous substances after isolation. It has been suggested that exosomes could be used as natural drug carriers to transport therapeutic agents across the BBB and have great potential for CNS disease therapy by promoting tissue regeneration and repair. Herein, we discuss perspectives on therapeutic strategies to treat neurodegenerative disease or spinal cord injury using a variety of cell types-derived exosomes with kinds of exosomal contents, as well as engineering strategies of specific functional and exosome administration routes.

The extracellular matrix (ECM) is a natural microenvironment pivotal for stem cell survival, as well as proliferation, differentiation and metastasis, composed of a variety of biological molecular complexes secreted by resident cells in tissues and organs. Heparan sulfate proteoglycan (HSPG) is a type of ECM protein that contains one or more covalently attached heparan sulfate chains. Heparan sulphate chains have high affinity with growth factors, chemokines and morphogens, acting as cytokine-binding domains of great importance in development and normal physiology. Herein, we constructed endogenous HSPG2 overexpression in mouse embryonic fibroblasts based on the CRISPR/Cas9 synergistic activation mediator system and then fabricated a cell-derived HSPG2 functional ECM (ECM^HSPG2). The ECM^HSPG2 is capable of enriching basic fibroblast growth factor (bFGF), which binds more strongly than the negative control ECM. With a growing bFGF concentration, ECM^HSPG2 could better maintain neural stem cell (NSCs) stemness and promote NSC proliferation and differentiation in culture. These findings provide a precise design strategy for producing a specific cell-derived ECM for biomaterials in research and regenerative medicine.

Glioma is one of the primary malignant brain tumours in adults, with a poor prognosis. Pharmacological reagents targeting glioma are limited to achieve the desired therapeutic effect due to the presence of blood‐brain barrier (BBB). Effectively crossing the BBB and specifically targeting to the brain tumour are the major challenge for the glioma treatments. Here, we demonstrate that the well‐defined small extracellular vesicles (sEVs) with dual‐targeting drug delivery and cell‐penetrating functions, modified by Angiopep‐2 and trans‐activator of transcription peptides, enable efficient and specific chemotherapy for glioma. The high efficiency of engineered sEVs in targeting BBB and glioma was assessed in both monolayer culture cells and BBB model in vitro, respectively. The observed high targeting efficiency was re‐validated in subcutaneous tumour and orthotopic glioma mice models. After loading the doxorubicin into dual‐modified functional sEVs, this specific dual‐targeting delivery system could cross the BBB, reach the glioma, and penetrate the tumour. Such a mode of drug delivery significantly improved more than 2‐fold survival time of glioma mice with very few side effects. In conclusion, utilization of the dual‐modified sEVs represents a unique and efficient strategy for drug delivery, holding great promise for the treatments of central nervous system diseases.

Enhancing neurogenesis of neural stem cells (NSCs) is crucial in stem cell therapy for neurodegenerative diseases. Within the extracellular microenvironment, extracellular matrix (ECM) plays a pivotal role in modulating cell behaviors. However, a single ECM biomaterial is not sufficient to establish an ideal microenvironment. As multifunctional nanocarriers, exosomes display tremendous advantages for the treatments of various diseases. Herein, collagen binding domain peptide-modified exosomes (CBD-Exo) were obtained from the SH-SY5Y cell line infected with lentivirus particles encoding CBD-lysosome associated membrane glycoprotein 2b (CBD-Lamp2b) to improve the binding efficiency of exosomes and ECM. An exosomes-functionalized ECM (CBD-Exo/ECM) was then constructed via the interaction between CBD and collagen in ECM. Then, CBD-Exo/ECM was employed as a carrier for NSCs culture. The results showed that CBD-Exo/ECM can support the neurogenesis of NSCs with the percentage of proliferation marker EdU-positive (35.8% ± 0.47% vs 21.9% ± 2.32%) and neuron maker Tuj-1-positive (55.8% ± 0.47% vs 30.6% ± 2.62%) were both significantly increased in the exosomes-functionalized ECM system. This exosomes-functionalized ECM was capable to promote the cell proliferation and accelerate neuronal differentiation of NSCs, providing a potential biomedical material for stem cell application in tissue engineering and regenerative medicine.

Minimal invasive phototherapy utilising near-infrared (NIR) laser to generate local reactive oxygen species (ROS) and heat has few associated side effects and is a precise treatment in cancer therapy. However, high-efficiency and safe phototherapeutic tumour agents still need developing. The application of iron hydroxide/oxide immobilised on reduced graphene oxide (FeOxH–rGO) nanocomposites as a therapeutic agent in integration photodynamic cancer therapy (PDT) and photothermal cancer therapy (PTT) was discussed. Under 808 nm NIR irradiation, FeOxH–rGO offers a high ROS generation and light-to-heat conversion efficiency because of its strong NIR absorption. These phototherapeutic effects lead to irreversible damage in FeOxH–rGO-treated T47D cells. Using a tumour-bearing mouse model, NIR ablated the breast tumour effectively in the presence of FeOxH–rGO. The tumour treatment response was evaluated to be 100%. We integrated PDT and PTT into a single nanodevice to facilitate effective cancer therapy. Our FeOxH–rGO, which integrates the merits of FeOxH and rGO, displays an outstanding tumoricidal capacity, suggesting the utilization of this nanocomposites in future medical applications.