The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been used to treat diseases. Growing evidence indicates that EVs play a cardioprotective role in heart disease by activating beneficial signaling pathways. Multiple functional components of EVs and intracellular molecular mechanisms are involved in the process. To overcome the shortcomings of native EVs such as their heterogeneity and limited tropism, a series of engineering approaches has been developed to improve the therapeutic efficiency of EVs. In this review, we present an overview of the research and future directions for EVs-based cardiac therapies with an emphasis on EVs-mediated delivery of therapeutic agents. The advantages and limitations of various modification strategies are discussed, and possible opportunities for improvement are proposed. An in-depth understanding of the endogenous properties of EVs and EVs engineering strategies could lead to a promising cell-free therapy for cardiac repair.

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Extracellular Vesicles: A New Frontier for Cardiac Repair

Redox imbalance can trigger cell dysfunction and damage and plays a vital role in the origin and progression of many diseases. Maintaining the balance between oxidants and antioxidants in vivo is a complicated and arduous task, leading to ongoing research into the construction of redox nanomaterials. Nanodrug platforms with redox characteristics can not only reduce the adverse effects of oxidative stress on tissues by removing excess oxidants from the body but also have multienzyme-like activity, which can play a cytotoxic role in tumor tissues through the catalytic oxidation of their substrates to produce harmful reactive oxygen species such as hydroxyl radicals. In this review, various redox nanomaterials currently used in disease therapy are discussed, emphasizing the treatment methods and their applications in tumors and other human tissues. Finally, the limitations of the current clinical application of redox nanomaterials are considered.

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The progress of research on the application of redox nanomaterials in disease therapy

Simple Summary Heart disease is the leading cause of death, globally. Cardiomyocytes in adult mammalian hearts lose their capacity to divide. Therefore, the loss of heart muscles after a heart attack is usually irreversible. Many novel therapies that aim to repair injured myocardium have been reported in the last few decades. In this field, there is an urgent need to develop a targeted drug delivery system that specifically delivers therapeutic agents to injured hearts. Nanoparticles are the most commonly used vehicles for targeted drug delivery in preclinical and clinical studies. Here, we provide the field with a comprehensive review of the latest strategies involving nanoparticle-based cardiac-specific drug delivery for the treatment of heart diseases. Abstract Heart failure secondary to myocardial injuries is a leading cause of death worldwide. Recently, a growing number of novel therapies have emerged for injured myocardium repairment. However, delivering therapeutic agents specifically to the injured heart remains a significant challenge. Nanoparticles are the most commonly used vehicles for targeted drug delivery. Various nanoparticles have been synthesized to deliver drugs and other therapeutic molecules to the injured heart via passive or active targeting approaches, and their targeting specificity and therapeutic efficacies have been investigated. Here, we summarized nanoparticle-based, cardiac-specific drug delivery systems, their potency for treating heart diseases, and the mechanisms underlying these cardiac-targeting strategies. We also discussed the clinical studies that have employed nanoparticle-based cardiac-specific drug delivery.

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Nanoparticle Based Cardiac Specific Drug Delivery

Neuropathic pain, which results from damage to the somatosensory nervous system, is a global clinical condition that affects many people. Neuropathic pain imposes significant economic and public health burdens and is often difficult to manage because the underlying mechanisms remain unclear. However, mounting evidence indicates a role for neurogenic inflammation and neuroinflammation in pain pattern development. There is increasing evidence that the activation of neurogenic inflammation and neuroinflammation in the nervous system contribute to neuropathic pain. Altered miRNA expression profiles might be involved in the pathogenesis of both inflammatory and neuropathic pain by regulating neuroinflammation, nerve regeneration, and abnormal ion channel expression. However, the lack of knowledge about miRNA target genes prevents a full understanding of the biological functions of miRNAs. At the same time, an extensive study on exosomal miRNA, a newly discovered role, has advanced our understanding of the pathophysiology of neuropathic pain in recent years. This section provides a comprehensive overview of the current understanding of miRNA research and discusses the potential mechanisms of miRNAs in neuropathic pain.

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Emerging roles of miRNAs in neuropathic pain: From new findings to novel mechanisms

Pirtobrutinib (JaypircaTM), a highly selective, non-covalent, reversible Bruton’s tyrosine kinase (BTK) inhibitor, is being developed by Eli Lilly and Company (Lilly) for the treatment of B-cell leukemias and lymphomas. In January 2023, pirtobrutinib was approved in the USA under the Accelerated Approval pathway for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. This article summarizes the milestones in the development of pirtobrutinib leading to this first approval for the treatment of adult patients with relapsed or refractory MCL. 

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Pirtobrutinib: First Approval

Abstract Background At present, patients with myocardial infarction remain an increased risk for myocardial ischemia/reperfusion injury (MI/RI). There lacks effectively method to treat MI/RI in clinic. For the treatment of MI/RI, it is still a bottleneck to effectively deliver drug to ischemic myocardium. In this paper, a regulatory T cells (Tregs) biomimetic nanoparticle (CsA@PPTK) was prepared by camouflaging nanoparticle with platelet membrane. Results CsA@PPTK actively accumulated in ischemic myocardium of MI/RI mice. CsA@PPTK significantly scavenged reactive oxygen species (ROS) and increased the generation of Tregs and the ratio of M2 type macrophage to M1 type macrophage in ischemic myocardium. Moreover, CsA@PPTK significantly attenuated apoptosis of cardiomyocytes and reduced the infarct size and fibrosis area in ischemic myocardium. CsA@PPTK markedly decreased the protein expression of MMP-9 and increased the protein expression of CX43 in ischemic myocardium tissue. Subsequently, the remodeling of the left ventricle was significant alleviated, and heart function of MI/RI mice was markedly improved. Conclusion CsA@PPTK showed significant therapeutic effect on MI/RI, and it has great potential application in the treatment of MI/RI. Graphical Abstract 

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Tregs biomimetic nanoparticle to reprogram inflammatory and redox microenvironment in infarct tissue to treat myocardial ischemia reperfusion injury in mice

Abstract Background Ischemic stroke is one of the main causes of death and disability in the world. The treatment for ischemic stroke is to restore blood perfusion as soon as possible. However, when ischemic brain tissue is re-perfused by blood, the mitochondrial permeability transition pore (mPTP) in neuron and microglia is excessively opened, resulting in the apoptosis of neuron and nerve inflammation. This aggravates nerve injury. Cyclosporine A (CsA) inhibits the over-opening of mPTP, subsequently reducing the release of ROS and the apoptosis of cerebral ischemia/reperfusion injured neuron and microglia. However, CsA is insoluble in water and present in high concentrations in lymphatic tissue. Herein, cerebral infarction tissue targeted nanoparticle (CsA@HFn) was developed to treat cerebral ischemia/reperfusion injury. Results CsA@HFn efficiently penetrated the blood-brain barrier (BBB) and selectively accumulated in ischemic area, inhibiting the opening of mPTP and ROS production in neuron. This subsequently reduced the apoptosis of neuron and the damage of BBB. Consequently, CsA@HFn significantly reduced the infarct area. Moreover, CsA@HFn inhibited the recruitment of astrocytes and microglia in ischemic region and polarized microglia into M2 type microglia, which subsequently alleviated the nerve inflammation. Conclusions CsA@HFn showed a significant therapeutic effect on cerebral ischemia/reperfusion injury by alleviating the apoptosis of neuron, nerve inflammation and the damage of BBB in ischemic area. CsA@HFn has great potential in the treatment of ischemic stroke. Graphical Abstract 

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Cyclosporine A loaded brain targeting nanoparticle to treat cerebral ischemia/reperfusion injury in mice

Platelets are the second most abundant blood component after red blood cells and can participate in a variety of physiological and pathological functions. Beyond its traditional role in hemostasis and thrombosis, it also plays an indispensable role in inflammatory diseases. However, thrombocytopenia is a common hematologic problem in the clinic, and it presents a proportional relationship with the fatality of many diseases. Therefore, the prevention and treatment of thrombocytopenia is of great importance. The expression of Toll-like receptors (TLRs) is one of the most relevant characteristics of thrombopoiesis and the platelet inflammatory function. We know that the TLR family is found on the surface or inside almost all cells, where they perform many immune functions. Of those, TLR2 and TLR4 are the main stress-inducing members and play an integral role in inflammatory diseases and platelet production and function. Therefore, the aim of this review is to present and discuss the relationship between platelets, inflammation and the TLR family and extend recent research on the influence of the TLR2 and TLR4 pathways and the regulation of platelet production and function. Reviewing the interaction between TLRs and platelets in inflammation may be a research direction or program for the treatment of thrombocytopenia-related and inflammatory-related diseases.

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Toll-like Receptors and Thrombopoiesis

Therapeutic effect and underlying mechanism of Shenkang injection against cisplatin-induced acute kidney injury in mice.

Thrombocytopenia is a thrombopoietin (TPO)-related disorder with very limited treatment options, and can be life-threatening. There are major problems with typical thrombopoietic agents targeting TPO signaling, so it is urgent to discover a novel TPO-independent mechanism involving thrombopoiesis and potential druggable targets. We developed a drug screening model by the multi-grained cascade forest (gcForest) algorithm and found that 3,8-di-O-methylellagic acid 2-O-glucoside (DMAG) (10, 20 and 40 µM) promoted megakaryocyte differentiation in vitro. Subsequent investigations revealed that DMAG (40 mM) activated ERK1/2, HIF-1b and NF-E2. Inhibition of ERK1/2 blocked megakaryocyte differentiation and attenuated the upregulation of HIF-1b and NF-E2 induced by DMAG. Megakaryocyte differentiation induced by DMAG was inhibited via knockdown of NF-E2. In vivo studies showed that DMAG (5 mg/kg) accelerated platelet recovery and mega-karyocyte differentiation in mice with thrombocytopenia. The platelet count of the DMAG-treated group recovered to almost 72% and 96% of the count in the control group at day 10 and 14, respectively. The platelet counts in the DMAG-treated group were almost 1.5- and 1.3-fold higher compared with those of the irradiated group at day 10 and 14, respectively. Moreover, DMAG (10, 25 and 50 mM) stimulated thrombopoiesis in zebrafish. DMAG (5 mg/kg) could also increase platelet levels in c-MPL knockout (c-MPL-/-) mice. In summary, we established a drug screening model through gcForest and demonstrated that DMAG promotes megakaryocyte differentiation via the ERK/HIF1/NF-E2 pathway which, importantly, is independent of the classical TPO/c-MPL pathway. The present study may provide new insights into drug discovery for thrombopoiesis and TPO-independent regulation of thrombopoiesis, as well as a promising avenue for thrombocytopenia treatment.

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Targeting a thrombopoietin-independent strategy in the discovery of a novel inducer of megakaryocytopoiesis, DMAG, for the treatment of thrombocytopenia

Qibing Mei

Papers

Tregs biomimetic nanoparticle to reprogram inflammatory and redox microenvironment in infarct tissue to treat myocardial ischemia reperfusion injury in mice

Cyclosporine A loaded brain targeting nanoparticle to treat cerebral ischemia/reperfusion injury in mice

Toll-like Receptors and Thrombopoiesis

Therapeutic effect and underlying mechanism of Shenkang injection against cisplatin-induced acute kidney injury in mice.

Targeting a thrombopoietin-independent strategy in the discovery of a novel inducer of megakaryocytopoiesis, DMAG, for the treatment of thrombocytopenia