Ischemic diseases, especially in the heart and the brain, have become a serious threat to human health. Growth factor and cell therapy are emerging as promising therapeutic strategies; however, their retention and sustainable functions in the injured tissue are limited. Self-assembling peptide (SAP)-based hydrogels, mimicking the extracellular matrix, are therefore introduced to encapsulate and controllably release cells, cell-derived exosomes or growth factors, thus promoting angiogenesis and tissue recovery after ischemia. We will summarize the classification, composition and structure of SAPs, and the influencing factors for SAP gelation. Moreover, we will describe the functionalized SAPs, and the combinatorial therapy of cells, exosomes or growth factors with functionalized SAPs for angiogenic process as well as its advantage in immunogenicity and injectability. Finally, an outlook on future directions and challenges is provided.

Deep vein thrombosis (DVT) is caused by blood clotting in the deep veins. Thrombosis resolution and recanalization can be accelerated by endothelial progenitor cells. In this report, we investigated the effects of miR-126-loaded EPC-derived exosomes (miR-126-Exo) on EPCs function and venous thrombus resolution. In vitro promotional effect of miR-126-Exo on the migration and tube incorporation ability of EPCs was investigated via transwell assay and tube formation assay. In addition, a mouse venous thrombosis model was constructed and treated with miR-126-Exo to clarify the therapeutic effect of miR-126-Exo by histological analysis. Lastly, this study predicted a target gene of miR-126 using target prediction algorithms and confirmed it by luciferase activity assay, RT-qPCR, and Western blot. Transwell assay and tube formation assay indicated that miR-126-Exo could enhance the migration and tube incorporation ability of EPCs. Moreover, in vivo study manifested enhanced thrombus organization and recanalization after miR-126-Exo treatment. Meanwhile, we identified that Protocadherin 7 as a target gene of miR-126. To sum up, our results demonstrated that EPC-derived exosomes loaded with miR-126 significantly promoted thrombus resolution in an animal model of venous thrombosis, indicating exosomes as a promising potential vehicle carrying therapeutic molecules for DVT therapy.

Background: Abdominal aortic aneurysms (AAAs) are a global health and economic burden. Therapeutic strategies to inhibit the progression of AAAs are currently lacking. Recently, the therapeutic effect of metformin on aneurysms has attracted considerable interest. However, the unfavorable pharmacokinetic properties of metformin limit its feasibility for AAA treatment. Methods and Results: We constructed a metformin-loaded netrin-1-responsive AAA-targeted nanoparticle (Tgt-NP-Met) for AAA management. Evaluation of the therapeutic effect of Tgt-NP-Met was performed by in vitro and in vivo experiments. Our results showed that the binding of netrin-1 monoclonal antibodies enhanced the AAA-targeting capability of nanoparticles (NPs). Moreover, Tgt-NP-Met administration prevented AAA development and reduced the aneurysm diameter in apolipoprotein E (ApoE)-deficient (ApoE^−/−) mice that received continuous infusion of angiotensin II. Furthermore, metformin prevented AAA progression by inhibiting the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, which is mediated by macrophage infiltration and activation. Conclusion: Our findings identify metformin as a functional suppressor for macrophage-mediated phenotypic transformation of VSMCs and Tgt-NP-Met as an efficient therapeutic strategy for AAA management. Graphical Abstract:

Abdominal aortic aneurysm (AAA) is a life-threatening vascular condition. Currently, there are no clinically available pharmacological interventions that can stop the progression of AAA, primarily due to the incomplete understanding of its pathogenesis and the absence of effective drug delivery systems. The present study aimed to develop a targeted therapy for AAA through a nanomedicine approach involving site-specific regulation of neutrophil extracellular trap (NET)-related pathological vascular remodeling. We found that metallothionein 1 (MT1) was upregulated in AAA lesions in both humans and mice. MT1 also facilitated the formation of NETs and subsequently induced phenotypic transformation and apoptosis in vascular smooth muscle cells. Additional in vivo studies revealed that the glycoRNA-rich membranes coated siMT1-loaded poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) nanoparticles (GlycoRNA-NP-siMT1) effectively delivered siMT1 to AAA lesions, thereby inhibiting abdominal aortic dilation. Mechanistically, GlycoRNA-NP-siMT1 mitigated pathological remodeling of the abdominal aorta by reducing neutrophil infiltration and inhibiting the formation of NETs. Our study indicates that MT1 facilitates the progression of AAA by modulating the formation of NETs. Furthermore, GlycoRNA-NP-siMT1 show an inhibitory effect on AAA progression through a dual mechanism: they competitively inhibit neutrophil infiltration and release siMT1, which subsequently suppresses NET formation.