MI is a critical cardiology condition threatening patients' lives. The root lies in the heart's poor self-repair ability, causing irreversible damage after injury and a narrow survival window post-ischemia [1]. Ischemia leads to loss of systolic function and the formation of scar tissue, which weakens the heart and can cause heart failure (HF) [2]. HF, a manifestation of various cardiovascular diseases, affects about 40 million people globally with a 1% - 2% prevalence [3]. As the population ages, its prevalence will rise, burdening the medical system [4]. Currently, clinical HF treatments mainly include heart transplantation, drug therapy, and medical instrument interventional therapy [5]. Heart transplantation, the “gold standard”, is limited by donor shortages and post-transplantation complications [6]. Other therapies can improve heart function to some extent but cannot fully inhibit or reverse HF progression, resulting in limited effects [7]. Given these limitations, exploring new therapeutic approaches for HF is urgent. This can benefit patients and the global healthcare system.

As an important branch of modern medicine, tissue engineering and regenerative medicine technology have opened up a new avenue for the treatment of heart failure, a complex and intractable disease, which shows great promise and offers numerous potential treatment options [8]. Among them, injectable hydrogels have been widely used in drug delivery therapy according to different pathological characteristics [9]. The liquid carrier gel can realize the timed and quantitative release of the drug according to the needs of the diseased site, to improve the pertinency and effectiveness of the drug [10]. As a carrier material, hydrogels usually have good biocompatibility and can reduce the irritation and adverse reactions of drugs to the body. The characteristics of the microenvironment in the early stage of MI mainly include the enhancement of oxidative stress, the peak of the inflammatory response, and the damage and necrosis of myocardial cells caused by ischemia. Therefore, it is a wise choice to carry out drug delivery according to these pathological features [11]. In recent years, some researchers have treated MI with potion-carrying gels. For example, Wu and Liu et al. synthesized endothelial-loaded hydrogels for the treatment of ischemia during MI to achieve the effect of MI treatment [12,13]. Yang et al. synthesized loaded nanoparticles coated with antioxidants to improve cardiac function by treating intense oxidative stress during MI [14]. These studies used hydrogels coated with drugs or growth factors to treat MI. At present, the synthetic antioxidants used, such as BHA (butylhydroxyanisole), BHT (dibutylhydroxytoluene), PG (propyl gallate), and TBHQ (tert-butylhydroquinone), have certain toxic side effects on the human body, and there are problems of low antioxidant efficiency and narrow application range [[15], [16], [17]]. In addition, the growth factor used for treatment as a drug therapy has significant effects in some aspects, but it also has some shortcomings [[18], [19], [20], [21]]. The production of growth factors involves complex biotechnology, resulting in high research and development and manufacturing costs.

Peptides are bioactive molecules formed by short-chain amino acids connected by peptide bonds, which have the characteristics between small molecule drugs and large molecule biological products [22]. They have high biological activity and specificity, low immunogenicity, and high purity. These characteristics make peptide products a wide application prospect in drug development [23]. At present, with continuous research, peptides with various functions have been developed, such as anti-inflammatory peptides, antioxidant peptides, antimicrobial peptides, anti-tumor peptides, etc., whose main applications are reflected in medicine, health products, food, cosmetics, and other fields [[24], [25], [26]]. Nature-derived peptides are involved in regulating many physiological functions of the human body. They can affect the physiological activities of nerves, digestion, absorption, metabolism, circulation, and endocrine, and are closely related to human health. For example, some nature-derived peptides can lower blood pressure, blood sugar, and blood lipids, and have potential value for the prevention and treatment of chronic diseases such as cardiovascular disease and diabetes [25]. Antioxidants in fish also help prevent chronic diseases such as cardiovascular disease and cancer [27]. For example, omega-3 fatty acids can lower blood cholesterol and triglyceride levels, thereby preventing cardiovascular disease [28]. These facts prove that functional peptides play an increasingly important role in the field of life and health.

With so many advantages of peptides, the benefits of nature-derived peptides for humans are obvious. Inspired by this, MMP12 (YWDAW), a peptide derived from deep-sea fish, was employed to treat oxidative stress in the microenvironment at the beginning of MI. On the other hand, G protein-coupled receptors of the endothelial differentiation gene (EDG) family mediate pro-angiogenic activities, including endothelial cell proliferation, migration, and vascular morphogenesis [29]. Thus, the specific peptide KRX (MRPYDANKR), derived from one of the sequences of the EDG, was also utilized. These two bioactive peptides of natural origin were combined with methyl acrylamide gelatin (GelMA), which exhibits equally good biocompatibility, to obtain the bioactive peptide-based composite hydrogel. Compared with previously reported materials, such as drug delivery systems or functional materials fabricated from other organic or inorganic substances, our bioactive peptide hydrogel demonstrates superior clinical application prospects primarily due to its exceptional biodegradability and biosafety. Following functional execution, the bioactive peptides are degraded into amino acids, which are intrinsic components of human tissues, thereby eliminating concerns regarding potential side effects and metabolic complications. In conclusion, the bioactive peptide hydrogel not only exhibits remarkable therapeutic efficacy in myocardial infarction treatment but also possesses inherent biosafety that represents its most significant advantage and promising prospect for clinical applications. The multifunctional composite hydrogel can reduce ROS levels, inhibit cell apoptosis, and effectively inhibit inflammation due to the MMP 12 peptide. At the same time, the KRX peptide in the hydrogel can also promote the proliferation, migration, and angiogenesis of HUVE cells at the site of MI. In addition, the process of the interaction of these two peptides has also been found to inhibit myocardial fibrosis to a certain extent. By increasing CD206, CD31, VWF, and type III collagen and decreasing ROS, CD86 and type I collagen, the bioactive peptide-based composite hydrogel can implement a comprehensive treatment plan of anti-oxidation, anti-apoptosis, anti-inflammatory, pro-vascular and anti-fibrosis. Bioactive peptide-based composite hydrogel can significantly accelerate the repair process of a damaged heart under inflammatory conditions and effectively repair MI.

In this study, we developed a multifunctional hydrogel (Gel@MK) incorporating short-chain antioxidant peptides (derived from deep-sea fish) and short-chain pro-angiogenic peptides (derived from mammals), offering a novel, safe, and efficient therapeutic strategy for MI (Scheme 1). The synergistic effect of antioxidative stress and pro-angiogenesis has been widely reported to significantly enhance myocardial repair. While numerous studies have developed various functional materials, including pharmaceutical agents and nanozymes, to achieve ROS scavenging and angiogenesis promotion with considerable therapeutic outcomes, our hydrogel system demonstrates unique advantages for clinical translation. Specifically, the utilization of natural-origin peptides in our system not only ensures effective therapeutic performance but also offers superior biocompatibility, including low immunogenicity and excellent biodegradability. Unlike synthetic materials that may raise concerns about metabolic byproducts and long-term safety, our peptide-based hydrogel can be safely metabolized into endogenous amino acids, eliminating potential safety concerns. These distinctive features, combined with its demonstrated therapeutic efficacy, position our hydrogel system as a particularly promising candidate for clinical applications in myocardial infarction treatment.