ECM isa complex framework constructed by a various biomolecule around cells to maintain the natural physiological function of myocardiocytes and the physiological structure of the heart (Wang X et al., 2021). The activation of inflammation leads to the release of (MMP), which leads to the degradation and remodeling of ECM. Subsequently, collagen is continuously deposited in the ECM, and necrotic cardiac tissue is permanently replaced by fibrotic ECM. On the contrary, the restoration of normal physiological function and structure of ECM has now been shown to be beneficial to myocardial fibrosis (X. Wang et al., 2022). At present, biomaterials are currently applied to restore the ECM with functions including re-establishing microenvironmental blood flow, providing mechanical support, softening the fibrotic ECM, and protecting cardiomyocyte (Y. Li et al., 2021; Ozbek, Balasubramanian, Chiquet-Ehrismann, Tucker, and Adams, 2010; Rodell et al., 2016).

Intramyocardial or epicardial transplantation of cardiomyocytes or stem cells can maintain or even restore cardiac function in a paracrine like manner, or can restore lost cell populations (Hatzistergos et al., 2010; Bargehr et al., 2019). Previous studies have demonstrated that cardiomyocyte-derived cells (CDCs), induced pluripotent stem cells (iPSCs), embryonic cells, endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs) have a positive effect on the repair of damaged myocardium (Bierie et al., 2009; J. Chen et al., 2018; Kisseleva and Brenner, 2021; Laflamme et al., 2007; Pittenger and Martin, 2004). PSCs may differentiate into all types of somatic cells and subsequently repair multiple tissues (Weiskirchen, Weiskirchen, and Tacke, 2019). Both adipose-derived MSCs and amniotic-derived MSCs were utilized for repairing myocardial injury (Y. Chen et al., 2020; You et al., 2021). MSCs can consistently produce and release therapeutic molecules that control apoptosis, inflammatory response through paracrine signaling, accompanied by cytokine upregulation such as HIF1-α, IL-10, TIMP-1, MMP-2, IGF-1, CXC12 and FGF-2, which can realize inhibition of inflammation, inhibit extracellular matrix remodeling, and achieve blood supply reconstitution (Figure 3)(Gnecchi et al., 2006; You et al., 2021). Alternatively, stem cell-related technologies can be used to improve the therapeutic effect of stem cells and repair lost cell populations to a certain extent through direct programming or paracrine signaling by cell injection (Awada et al., 2017). Previously, MSCs were often delivered by direct injection, such as intracardiac, intravenous, or coronary catheter delivery (Melhem et al., 2017). However, such an injection method suffers from low retention rates of cell transplantation and poor long-term cell survival (Zeng et al., 2007). The use of injectable hydrogels or cardiac patches allows for excellent delivery of cells and minimizes cell displacement. It also provides a normal growth environment for stem cells and maintains cell viability and secretory activity (Mirotsou, Jayawardena, Schmeckpeper, Gnecchi, and Dzau, 2011; Chi et al., 2012; Mewhort, Turnbull, Meijndert, Ngu, and Fedak, 2014). Stem cell therapy is one of the current promising methods to repair partially missing myocardium, capable of achieving a variety of beneficial cardiomyocyte and ECM functions through paracrine like secretion. However, the excessive cost and huge risk of transplantation make people doubt its effectiveness and safety, and regulatory agencies have strict requirements for clinical trials of stem cells (J. Tang et al., 2022). Studies have also demonstrated that the tumorigenic risk, immune risk, and off-target effect of stem cell therapy existed (Heslop et al., 2015; J. N. Tang et al., 2018). Therefore, there are still many problems to be solved in stem cell therapy, but this is not a bad direction.

In recent years, with the continuous development of microRNA (miRNA) technology using miRNA as a target or miRNA as a therapeutic active ingredient to regulate cellular protein expression to treat myocardial fibrosis has achieved initial success. Researchers used CDR132(an antisense oligonucleotide) to specifically inhibit the function of miR-132, normalize cardiomyocytes, and prevent and reverse the pathological remodeling process of the myocardium. This is the first miRNA drug proved to be safe and effective in the treatment of HF. This study is also a milestone breakthrough in the application of miR in HF treatment (Nicholls, 2022). In addition, miRNAs can simultaneously promote the secretion of a variety of endogenous molecules which regulate various aspects of angiogenesis, inflammation, and cell differentiation (Y. Li et al., 2021). Several anti-apoptotic miRs, such as miR-24 and miR-214,related to cell proliferation, miR-19 and 590, and miR-210 related to cardiovascular generation, have been shown to be beneficial to myocardial recovery (J. Chen et al., 2013; Eulalio et al., 2012; Harel-Adar et al., 2011; Hu et al., 2010; Verma, 2013). However, the use of miRNAs for therapeutic purposes requires attention to the fact that exposed miRNAs need to be protected by encapsulation to prevent failure caused by cyclic degradation (Y. Li et al., 2021). Besides, miRNAs are required to enter the cell to perform their functions, so the delivery platform for miRNAs needs to be modified to increase cellular uptake (Bheri and Davis, 2019). Generally, miRNAs are negatively charged and can be bonded with biological materials for intracardiac delivery using electrostatic adsorption (Y. Li et al., 2021). Nucleic acids can modify the composition of local signaling molecules and enhance repair and regeneration, making it an ideal choice for effective biomolecules in myocardial injury (Sager et al., 2016). The mechanisms of miRNA therapies are more clearly defined than that of stem cell therapies. However, it is still worth considering whether therapeutic modalities that regulate the expression of a single gene to cope with the complex physiological environment could continue to be optimized.

Exosomes are nano-vesicles secreted by cells, which can encapsulate nucleic acids, proteins, lipids, amino acids, and other metabolites. As a “messengers” of proximal intercellular communication, exosomes can affect cells in both healthy and diseased states (Figure 4)(Kalluri and LeBleu, 2020). Cardiovascular exosomes are secreted by mesenchymal stem cells, pluripotent stem cells, cardiomyocyte-derived cells, etc. (Gao et al., 2020; Nguyen, Dawkins, Bi, Marbán, and Li, 2018; J. Tang et al., 2022). Exosomes derived from cardio sphere-derived cells (CDC) improve poor myocardial remodeling, inhibit fibrosis, and improve post-infarction cardiac function in pigs (Gallet et al., 2017). Reports have demonstrated that iPSC-derived exosomes can act on cardiomyocytes to reduce apoptosis, maintain calcium stability and promote vascular growth (Gao et al., 2020). In addition, some exosomes can also affect macrophages and regulate the polarization of macrophages to reduce the inflammatory response (Hu et al., 2021). Like cells, exosomes delivered to the heart degrade in a short time and cannot be retained in injuried area to obtain sustained effects. Therefore, the use of exosomes as therapeutic agents also requires consideration of the targeting, local retention capacity and biological activity of the inclusions (J. Yao et al., 2021). It is undeniable that exogenous therapy is conducive to the recovery of cardiomyocytes. However, exosomes are of diverse origin and contain complex contents, and are basically tools for intercellular communication. The specific effects of exosome regulation is influenced by the cells that secrete them (Kalluri and LeBleu, 2020). Due to the limitations of acquisition, preservation, transportation and safety, there are still many problems in clinical applications.

In addition to providing mechanical support, some natural gels have their own functions, and most of which come from ECM itself or materials with ECM-like composition (Table 1)(Y. Chen et al., 2020). Such functional materials are used to deliver effective molecules with therapeutic effects, and can simply achieve various therapeutic effects (Le et al., 2018). ECM of human- and porcine-derived cardiomyocytes has been used for the treatment of fibrosis after MI. The decellularized extracellular matrix (dECM), obtained by decellularization is rich in biologic factors, which can provide a cellular growth environment, softenten the microenvironment, maintain the normal function of normal cardiomyocytes, reduce the conversion of cardiac fibroblasts to myofibroblasts, decrease the expression of transforming growth factor-β (TGF-β), and reduce matrix collagen deposition (X. Wang et al., 2022; Wang X et al., 2021). Using natural gel to treat cardiomyocyte injury is theoretically very promising, but there are still some problems. Natural gels usually contain large amounts of peptides/proteins. Take dECM as an example, whether dECM of heterologous source tends lead to severe local immune response and contribute to further deterioration. However, due to the limitations of theory, cost and scope of application, there are also many problems that need to be solved before human derived dECM can be used in clinical treatment (Wang X et al., 2021)

Synthetic hydrogels for in vivo injection are usually synthesized from metabolizable materials (Table 2) and modified with hydrophilic groups to increase the void space of the gel to increase the drug loading capacity. Carboxyl groups such as polylactic acid and polyvinyl alcohol can increase hydrophilicity and degraded into monomers such as lactic acid, which can metabolize into carbon dioxide and water for excretion (Zheng et al., 2021). Some synthetic proteins, such as elastin mimetic peptide hydrogel (EMH) and type I collagen hydrogel, can metabolize normally and non-toxically in vivo. Due to the self-assembly characteristics of elastin mimetic peptide, they can repair themselves when damaged, so as to achieve long-term stable support effect and drug delivery (R. Chen et al., 2021). Poly(N-isopropylacrylamide), poly (N-isopropylacrylamide-co-polyacrylic acid), melamine cross-linked PEG, and some other materials containing amino groups are used for protein, peptide, and stem cell delivery (Bao et al., 2017; Mihalko et al., 2018; J. Tang et al., 2017). Take Poly(N-isopropylacrylamide) nanogels (FSN) as an example. The prevention and treatment of fibrosis require drugs to be released in a certain order and dynamically adjusted to improve the therapeutic effect and bioavailability of drugs. N-isopropylacrylamide (NIPAM) and N, N′-methylenebisacrylamide (BIS) are polymerized in a certain ratio, where NIPAM extends the main chain and provides hydrophilicity and BIS is used for cross-linking to form a mesh structure. The ratio of BIS affects the tightness of the crosslinking of the mesh structure, thereby affecting the degradation rate of the material at the damaged site, so as to achieve the gradual release effect (Figure 5A)(Mihalko et al., 2018). Due to the formation of scarring and fibrosis in the myocardial tissue, local electrical signal conduction is blocked, resulting in atrial and ventricular electrical signal rhythm disorders. In the long run, this will will affect the normal function of the heart, aggravate heart failure and lead to the reduction of left ventricular ejection fraction (He et al., 2020). Therefore, it is also necessary to increase the electrical conductivity of the gel. Polycarboxybetaine macromonomer polymerized with dithiothreitol (DTT) is an amphoteric material that can provide an environment for cell growth as well as conductive and antioxidant function (Liu Y et al., 2021). Artificial polymeric gel materials can achieve a variety of functionalities. In addition to the above gradual release and conductivity, they can also adjust the adhesion of materials (You et al., 2021), prolong the action time of materials, and protect deliverables from immune attack, etc. (Y. Chen et al., 2020; J. Tang et al., 2017)

Hydrogels need to provide mechanical support in the myocardium, as well as continuous drug release and cardiomyocyte protection, requiring a certain mechanical strength and slow degradation of the hydrogel in vivo. However, in order to achieve injectable hydrogels, it must be in a state that can flow in vitro. Realizing the transition from the injectable state in vitro to the gel state in vivo requires that the material be able to undergo a phase transition based on the microenvironmental state, namely gelation (Diaz et al., 2021). According to the pathological process of myocardial fibrosis, the local microenvironment of fibrosis at the site of acute and chronic myocardial injury is different from normal tissue in terms of pH, ROS, and enzymes, as well as the aqueous environment in vivo and the normal physiological temperature of the organism are not the same as in vitro. Therefore, the material design can refer to the environment of fibrotic tissues in myocardium. It can be simply divided into chemical process gelation and biological process gelation.

The chemical process gelation can respond to the aqueous environment in vivo, physiological temperature (37°C), and injection time. Gelation can also be achieved with the help of external conditions, such as light irradiation. Delivery system for co-delivery of miRNA by injectable hydrogel and mesoporous silica (Gel@MSN/miR-21-5p). Two types of interactions are utilized: i) hydrophobic interactions between cyclodextrins (CD) along aldehyde-based polyethylene glycol chains. ii) Schiff base reactions between amino groups from mesoporous silica and aldehyde-based polyethylene glycols (reaction of amino groups with aldehydes to form imine structures with the involvement of water), which cross-link to form network structures. The Schiff base reaction can also be used to achieve slow release of the delivery agent in response to the pH of the local inflammatory environment, to achieve polarization of macrophages to relieve inflammation and to increase blood supply to the local microenvironment (Y. Li et al., 2021). Responsive gelation can also be achieved using thermosensitive materials. Thermosensitive poly (N-isopropylacrylamide-co-polyacrylic acid) nanogels take advantage of the opposite rotation of the material under temperature change, and in vitro experiments have also been demonstrated that the material can gelate at 37°C to increase mechanical strength for delivery of hCSCs (J. Tang et al., 2017). In addition, modulating the gelation time of the material can enable in vivo injectability. For example, the Michael addition of thiols and alkenes was used in the previous study to construct polycarboxybetaine macromolecular monomers with dithiothreitol (DTT) polymerized materials (Liu Y et al., 2021). External aids can assist in gelation after gel injection. Using light irradiation, poly(2-alkyl-2-oxazoline) (POx) derivatives of 2-ethyl-2-oxazoline and 2-butenyl-2-oxazoline can be rapidly cured in less than 2 min. The tunable spatial structure of the synthetic gels allows their use for stem cell and protein/peptide delivery.

Decellularized extracellular matrix gels are a mature process in which decellularized extracellular matrix is obtained and digested by digestive enzymes to prepare an injectable extracellular matrix pre-gel, which is injected into the body and re-geled into the extracellular matrix state under physiological conditions (X. Wang et al., 2022; Wang X et al., 2021). Unlike the in vitro environment, the achievement of normal physiological functions of tissues involves the participation of a very large number of enzymes that are not present in the in vitro environment. As shown in Figure 5B, using a specific enzyme-substrate response design, the process of myocardial injury and fibrosis is accompanied by the increase of thrombin, and fibrinogen can coalesce into fibrin gel in the presence of thrombin. Fibrin gels based on this design involve heparin-loaded basic fibroblast growth factor-2 (FGF-2) and stromal cell growth factor-1α (SDF-1α) that are slowly released in the ECM to recruit stem cells and reestablish blood supply (Awada et al., 2017). The functionality of the enzyme can also be used to prepare cyclopeptide precursors, which are openedby the cleavage of metalloproteinase-2/9 (MMP-2/9) in vivo and repolymerized to form cross-linked protein gels (Figure 5C)(Carlini et al., 2019). The synthetic protein/peptide will be more biocompatible and able to be metabolically cleared. As with natural materials, protein gels can also be modified with proteins to obtain a material that is inherently beneficial for cardiac recovery. It can be used to deliver some cytokines, chemokines, and some small molecule drugs.

Most of the materials used to make cardiac patches are biocompatible and highly elastic materials. Polymer materials such as PEG, graphene, HA, polylactic acid, polyamino esters, chitosan, and some protein materials such as silk protein and type I collagen have been used for the manufacture of cardiac patches (Feng et al., 2021; Melhem et al., 2017; Xie et al., 2022; Y. Yao et al., 2022).Patches is a kind of biomaterial, which can provide structural stability for damaged tissues under physiological conditions and maintain the stability of active substances such as cells and proteins (Melhem et al., 2017). Compared with injectable hydrogel, cardiac patch biomaterials adhere better to the heart and provide better drug release and support (Kim et al., 2019). However, the use of cardiac patches require invasive methods, such as surgical hand implantation. The inconvenience of use also limits the transfer of cardiac patch to clinical application.

In stem cell therapy, the low retention rate of cell transplantation and the poor long-term survival of cells are the main problems of current cell therapy (J. Chen et al., 2018). As one of the optimal materials for stem cell therapy, patches provide an environment for stem cells to maintain normal function and longer retention time because of their better elasticity, cell viability and secretory activity (Kim et al., 2019). In one study, poly (ethylene glycol) dimethacrylate (PEGDMA) was designed with the aid of stereolithography (SLA) as a patch material with fixed pore sizes to accommodate to bone marrow-derived mesenchymal stem cells (MSCs) and maintain MSC cellular activity over time. Compared with patches loaded with MSCs without micropores, the ejection fraction and output per beat were improved (Melhem et al., 2017). Similarly, chitosan/silk proteins (CS/SF) multilayer modified electrostatically spun cellulose nanofiber patches enabled delivery of adipose-derived mesenchymal stem cells (AD-MSCs), thereby reducing local scarring, improving fibrotic status, decreasing cardiomyocyte apoptosis, and reconstructing blood supply in ECM (J. Chen et al., 2018).

Synthetic polymeric materials usually allow for some functionalization using the chemical structure of the polymer. In the early stages after acute myocardial injury, with the death of apoptotic cardiomyocytes, cell rupture increases the level of ROS in the local microenvironment. The ROS response can be achieved by inserting the structure of thioacetal ketone (PTK) and poly (propylene fumarate) (PPF) into elastic polyurethane (PFTU). In combination with pro-angiogenic Arg-Glu-Asp-Val (REDV) peptide and Rosuvastatin (PRR), excess ROS are exhausted, and the intelligent on-demand release of proteins and drugs is realized depending on the severity of injury, followed by REDV and PRR action during fibrosis to inhibit the fibrotic process. This delivery platform enables dynamic delivery of therapeutic components to target the pathological process of myocardial fibrosis (Xie et al., 2022; Y. Yao et al., 2022)

Cardiac patches make an ideal material for maintaining normal cellular function and are very suitable for therapeutic strategies that require long-term maintenance (Liu M et al., 2021). However, due to the limitations of its preparation cost, material preservation and implantation methods in its application, the use of patches is still limited. At the same time, most of the functions that can be achieved by the patch can also be achieved by injectable hydrogels. It is undeniable that patches has their own advantages, however, the clinical translation potential of cardiac patches has been controversial (K. Huang et al., 2020; J. Yao et al., 2021)

Natural material hydrogels are mainly loaded in the form of physical encapsulation such as cytokines, chemokines, enzymes and their inhibitors, and encapsulated cells. On the other hand, synthetic hydrogels, can also release small molecule drugs through chemical bonding reaction. Because some cytokines, such as basic fibroblast growth factor (FGF-2) can promote vascular growth, the transient release of a large number of cytokines has the possibility of inducing tumors. Therefore, when using this active molecule as a therapeutic agent, the release rate must be controlled (C. Fan et al., 2019). The polymerization tightness of the hydrogel can be modulated to accelerate the release rate of the drug, or it can be combined with natural macromolecules to achieve controlled release. In one study, FGF-2 and stromal cell growth factor (SDF-1α) were encapsulated in a cohesive layer of heparin, With the degradation of the heparin adhesive layer, FGF-2 is slowly released to promote angiogenesis, SDF-1 α Mesenchymal stem cells are recruited to achieve a variety of effects, such as inhibiting ECM degradation, rebuilding blood supply, and reducing fibrosis (Awada et al., 2017). Hydrogel modification by itself still has limitations, while hydrogel combined with nanoparticle delivery platform can achieve a variety of delivery functions. FGF-2 was designed as nanoparticles covalently linked by MMP-2/9 cleavable peptide plalga (TIMP) and glutathione S-transferase (GST), forming a bifunctional Mi responsive hydrogel The binding between GST and reduced glutathione (GSH) is utilized to increase drug delivery. While TIMP responds to MMP-2/9 cleavage to release the drug,it also inhibited MMP-2/9 overexpressed after myocardial injury (TIMP is a competitive substrate for MMPs)(C. Fan et al., 2019).Compared with other nano materials, hydrogels have irreplaceable advantages in of biocompatibility, mechanical support, and cell protection. However, using hydrogels alone cannot solve the problem of single type drug delivery and difficult functionalization. Therefore, combining the advantages of a variety of biological nano materials, the development of cardiac drug delivery platform is a promising direction.

Currently, gel material is the “best material” for cardiomyocyte damage repair. Compared with nanoparticles, patches, etc., injectable hydrogels can mimic the normal functional environment of cardiomyocytes to the maximum extent. As a drug delivery material, hydrogel itself has certain functionalities, such as regulation of inflammation, promotion of new blood vessel growth, softening of cardiac tissue, and so on. With the use of cytokines, chemokines, etc., it is expected to restore the normal finishing state of the ECM. In addition, natural and synthetic gels have their own advantages Natural hydrogels still have some unknown mechanisms to achieve better biological adaptability and good recovery of damaged tissues, while synthetic hydrogels can confer more functionalization. In addition, hydrogels can be combined with other organic and inorganic nanomaterials to achieve more intelligent treatment targeting the local environment of cardiomyocyte injury. As a traditional biomaterial, hydrogels still have great potential for development and improvement. It can be applied to some injurious diseases such as myocardial injury, joint injury, and so on Injectable hydrogels should be used as a base platform for developing more functional biomaterials, rather than an independent system.

Polymer nanoparticles are usually made of biodegradable materials, such as chitosan (CS), polylactic acid-ethanolic acid (PLGA), HA, amino acids (e.g., lysine), some amino ester materials, etc. It can be used for the synthesis of polymer nanoparticles (Hong et al., 2020; Mihalko et al., 2018; X. Wang et al., 2020; X. Zhang et al., 2022; Y. Zhang et al., 2021). By utilizing the hydrophilic, charge properties, conjugation, or covalent linkage of the material, polymers can load drugs in a variety of ways, so that drugs can be released according to the characteristics of local microenvironment (such as pH, ROS, temperature, etc.) t (e.g., pH, reactive oxygen species, temperature, etc.)(Li Y et al., 2020; X. Wang et al., 2020).

Based on this, a fibrin-specific poly(N-isopropylacrylamide) nanogels (FSNs) loaded with tissue fibrinogen activator (tPA)/cellular contractility inhibitor (Y-27632) have been developed using hydrophobic properties. FSNs can specifically recognize fibrin in damaged cardiac sites, enabling targeting and improve blood supply at the same time. They address the need to re-establish blood supply in the local microenvironment and inhibit myocardial fibrosis after I/R injury (Mihalko et al., 2018). The surface charge properties of polymers are determined by the specific groups on the surface. Nanoparticles with a large amount of amino groups present tend to carry a positive charge at physiological pH. On the contrary, polymer nanoparticles usually carry a large amount of carboxyl groups a partial negative charge at physiological pH. Dendritic polylysine (DGL), which can be used to carry the internal wrapping ofAMO-1 (a miRNA that exhibits negative electrical properties and is used to improve myocardial fibrosis) while the outer layer is attached to the negatively charged low molecular weight liver (LMWH). Reduces microthrombus formation in microvessels, delivers AMO-1 to cardiomyocytes through microvessels, and enhances uptake by cardiomyocytes in the infarct area (Figure 6A)(Hong et al., 2020). Nanoparticles use polymeric nanoparticles to achieve responsive release according to the local microenvironment of damaged cardiomyocytes. A branched poly(β-amino ester) with a built-in redox-responsive structural domain (achieved through disulfide bonds) that provides effective siRNA affinity through a multi-branched structure and is degraded by intracellular reduced glutathione (GSH) into small fragments upon internalization into rat cardiac microvascular endothelial cells (RCMECs) for on-demand release (X. Wang et al., 2020).In addition, nanoparticles can be degraded into small fragments through pH reaction, ROS reaction photothermal, and magnetic properties, which can be used as a nano-delivery platform to target cardiac fibrosis .

Compared with organic synthetic and natural nanoparticles, inorganic nanoparticles have some unique properties such as magnetic properties, long-term stability, etc. (Sharma, Filip, Zboril, and Varma, 2015). Inorganic nanoparticles are usually synthesized using some metallic materials, such as gold, silver, iron, titanium, and some lanthanide elements (Luther et al., 2020). Nanoparticles are composed of iron oxide and silica dioxide, silica dioxide binds to both antibodies through hydrazone bonds and captures extracellular vesicles through the CD63 antigen on the surface of the extracellular vesicles (EV). The damaged myocardial site is acidic at pH and the hydrazone bond is broken to release EVs, which enables the capture and release of exosomes under the control of an external magnetic field (S. Liu et al., 2020). Silicon dioxide, calcium carbonate, and carbon materials can also be used to build nanoparticles (Zhu et al., 2016; Luther et al., 2020). The mesoporous silica-rich hollow structure is used to load miRNAs, and cell membranes modified with FH peptide (a peptide with high affinity for tendin-C (TN-C) produced by cardiac fibroblasts) with active targeting ability are used to target myofibroblasts for direct cardiac cell reprogramming and transformation of fibroblasts into induced cardiomyocyte-like cells (Wang Q et al., 2021). Inorganic nanoparticles could perform a variety of functions. However, inorganic nanoparticles are widely distributed in the organism and are not easy to remove, which raises concerns about the potential risks of accumulation of inorganic nanoparticles in the body, as well as the risks of toxicity and teratogenicity (Sharma et al., 2015; Soenen, Parak, Rejman, and Manshian, 2015; Medici, Peana, Pelucelli, and Zoroddu, 2021). For its potential risks, preliminary material screening can be carried out through high-throughput screening combined with toxicological experiments (Nel et al., 2013). Modification of the surface of nanomaterials can also reduce the toxicity of the material to some extent, such as PEG modification, which will reduce the ability to adhere to the surface of particles and reduces phagocytosis (Figure 6B)(Han et al., 2018; Heuer-Jungemann et al., 2019; C. Yang, Tian, and Li, 2016). Although the toxicity of inorganic nanoparticles has been studied, the metabolic clearance of inorganic materials in the body has been an unsolvable problem from the beginning, and the aggregation of inorganic materials in the body is also the inevitable result of the use of inorganic nanoparticles; the clinical application of inorganic nanoparticles in myocardial injury related diseases still has a long way to go.

Liposome nanoparticles are composed of phospholipid bilayers with a biofilm-like structure, which can be used to load hydrophilic and hydrophobic drugs due to their amphiphilic structural properties. We can change the head and tail structure of liposomes to realize the functionalization of liposomes, such as prolonging the circulation time of liposomes, achieving active targeting, targeting microenvironmental response, and multifunctional liposomes (Y. Fan, Marioli, and Zhang, 2021; M. Li et al., 2019). Liposomes are commonly used to provide immunosuppressants in myocardial injury diseases. Targeting dendritic cells with liposomes and immunosuppressants encapsulated with myocardial injury-associated antigens, can induce specific immune tolerance and inhibit the transformation of cardiac fibroblasts stimulated by chronic inflammatory response into muscle fibroblasts Dendritic cells can “nest” at the site of myocardial injury, so liposome nanoparticles can target dendritic cells by subcutaneous injections (Kwon et al., 2021). However, due to its own stability, liposomes have low bioavailability of direct cardiovascular targeting, and surface optimization is again needed to increase cycle time and targeting capacity (Takahama et al., 2009; Ferreira et al., 2017). There are few studies on liposome delivery of drugs to cardiomyocytes, but liposome nanoparticles have advantages due to their cell membrane-like structure and good biocompatibility. Liposomal nanoparticles combined with the advantages of other materials may have a broad prospects in cardiac drug delivery.