Ischemic Microenvironment‐Responsive Therapeutics for Cardiovascular Diseases

Abstract

Cardiovascular diseases caused by ischemia are attracting considerable attention owing to its high morbidity and mortality worldwide. Although numerous agents with cardioprotective benefits have been identified, their clinical outcomes are hampered by their low bioavailability, poor drug solubility, and systemic adverse effects. Advances in nanoscience and nanotechnology provide a new opportunity to effectively deliver drugs for treating ischemia‐related diseases. In particular, cardiac ischemia leads to a characteristic pathological environment called an ischemic microenvironment (IME), significantly different from typical cardiac regions. These remarkable differences between ischemic sites and normal tissues have inspired the development of stimuli‐responsive systems for the targeted delivery of therapeutic drugs to damaged cardiomyocytes. Recently, many biomaterials with intelligent properties have been developed to enhance the therapeutic benefits of drugs for the treatment of myocardial ischemia. Strategies for stimuli‐responsive drug delivery and release based on IME include reactive oxygen species, pH‐, hypoxia‐, matrix metalloproteinase‐, and platelet‐inspired targeting strategies. In this review, state‐of‐the‐art IME‐responsive biomaterials for the treatment of myocardial ischemia are summarized. Perspectives, limitations, and challenges are also discussed for the further development of innovative and effective approaches to treat ischemic diseases with high effectiveness and biocompatibility.

Mitochondrial DNA Is a Vital Driving Force in Ischemia-Reperfusion Injury in Cardiovascular Diseases

“…This includes the following: The use of vectors for cardiac mitochondrial transplantation [ 183 – 186 ]: for example, EVs can facilitate the immediate transfer of mtDNA, and administration of mitochondria-rich EVs into the myocardium has been shown to have beneficial effects on in vivo cardiac function after MI [ 187 ]. A recent review article published by our laboratory details the therapeutic effects of nanodrugs and smart delivery systems in animal models of ischemic cardiomyopathy [ 188 ] Isolation of mutated mitochondria and transfer of mitochondria to the extracellular compartment [ 189 ] Generation of specific nucleic acid endonucleases to target and degrade mutated mtDNA [ 190 ] Restoration of normal DNA via repair and editing of mutated mtDNA [ 191 ] Maintenance of mitochondrial membrane stability enhances the safety of mtDNA [ 107 , 192 , 193 ] Attenuation of cardiovascular injury is via inhibition of mtDNA and PRR-binding inflammatory pathways, mainly the TLR9 inflammatory pathway [ 194 , 195 ], the NLRP3 inflammatory pathway [ 196 – 198 ] and the cGAS inflammatory pathway [ 199 ] There are cytoprotective effects of mitochondria-derived peptides encoded by mtDNA against CVD via maintenance of amitochondrial function and cell viability and alterations in nDNA expression during metabolic stress and cytotoxic injury [ 200 ] …”

“…This includes the following: The use of vectors for cardiac mitochondrial transplantation [ 183 – 186 ]: for example, EVs can facilitate the immediate transfer of mtDNA, and administration of mitochondria-rich EVs into the myocardium has been shown to have beneficial effects on in vivo cardiac function after MI [ 187 ]. A recent review article published by our laboratory details the therapeutic effects of nanodrugs and smart delivery systems in animal models of ischemic cardiomyopathy [ 188 ] Isolation of mutated mitochondria and transfer of mitochondria to the extracellular compartment [ 189 ] Generation of specific nucleic acid endonucleases to target and degrade mutated mtDNA [ 190 ] Restoration of normal DNA via repair and editing of mutated mtDNA [ 191 ] …”

“…The use of vectors for cardiac mitochondrial transplantation [ 183 – 186 ]: for example, EVs can facilitate the immediate transfer of mtDNA, and administration of mitochondria-rich EVs into the myocardium has been shown to have beneficial effects on in vivo cardiac function after MI [ 187 ]. A recent review article published by our laboratory details the therapeutic effects of nanodrugs and smart delivery systems in animal models of ischemic cardiomyopathy [ 188 ]…”

Neuregulin-1, a potential therapeutic target for cardiac repair

“…The ischemic and hypoxic myocardial microenvironment leads to myocardial injury, induces an inflammatory response ( Li et al, 2021 ), and initiates self-repair processes such as apoptosis and autophagy ( Steffens et al, 2020 ). In the endothelium, IR injury leads to activation of EC (i.e., expression of pro-inflammatory molecules), increased permeability and edema, and impaired vasodilation ( Wan and Rodrigues, 2016 ; Colliva et al, 2020 ; Wagner and Dimmeler, 2020 ).…”

Progress in Stimuli‐Responsive Biomaterials for Treating Cardiovascular and Cerebrovascular Diseases

“…[2] The majority of these diseases can affect the brain or therapeutic approaches (e.g., plain administration of thrombolytics) insufficient. [5,14,15] Acknowledging the role of nanotechnology in the biomedical field and CCVDs, in this review, we seek to elucidate the recent advances in the development of stimuli-responsive biomaterials for the treatment of these diseases, with a focused interest on ischemic stroke and coronary heart disease (CHD) (Figure 1). Since the biomaterials' field is extensive, we focus only on the two major representatives, i.e., NPs and hydrogels, robustly used for treating CCVDs.…”