Myocardial infarction (MI) poses a significant health threat worldwide, showing persistently high mortality and morbidity rates [1]. The sustained myocardial ischemia and hypoxia resulting from coronary artery occlusion can inevitably result in the substantial loss of cardiomyocytes (CMs), endothelial cells, and cardiac fibroblast. Given the very limited regenerative capacity of CMs, fibroblasts would proliferate and deposit excessive collagen fiber [2]. Consequently, post-infarct progression would inevitably undergo fibrotic scar formation, cardiac dysfunction, adverse remodeling, and ultimately heart failure. Despite the advancements in interventional and pharmacological therapies, the clinical outcomes remain unsatisfactory because they target only a single pathological feature, underscoring the pressing unmet medical needs for more effective treatment strategies [3].

Accumulating research has suggested that synergistically combining different regenerative properties to target more than one specific pathological event across the sequential phases can substantially enhance therapeutic outcomes in MI treatment [4]. During the initial inflammatory phase, excessive reactive oxygen species (ROS) generated in and around the ischemic myocardium triggers a severe immune response, and also leads to the prolonged persistent loss of CMs [5]. Timely regulation of oxidative stress is crucial to prevent sustained inflammation and the further deterioration of MI. Electrical conduction is essential for the rhythmic contraction of our heart. With the substantial loss of CMs and the replacement of non-conductive fibrotic scar, abnormal electrical signal propagation occurs, inducing arrhythmogenic inhomogeneous electrophysiological distribution and asynchronous ventricular contractions. Therefore, preserving proper electrical signal conduction is vital for effective myocardial regeneration [6]. Furthermore, inadequate angiogenesis during MI healing presents a critical obstacle due to the heart's high metabolic demands. Enhanced neovascularization plays a pivotal role in replenishing oxygen and nutrients as well as clearing metabolic waste, thus mitigating the pathological deterioration and promoting MI repair [7,8]. Of paramount importance is the need for novel therapies that can simultaneously regulate excessive ROS, reconstruct electrical signal conduction, and promote angiogenesis.

Among the innovative regenerative therapies, such as cell therapy, gene therapy, and exosome therapy, biomaterials—especially injectable hydrogels—have emerged as an appealing paradigm in MI treatment [3,9]. Injectable hydrogels can be endowed with desired regenerative properties through advanced functionalization and hybridization with bioactive substances [10,11]. Consequently, some injectable hydrogels exhibiting antioxidant, electroactivity, or pro-angiogenic properties have been developed to improve MI healing efficacy through synergistic effects. However, to date, the methodologies for fabricating injectable hydrogels featuring multiple desired regenerative traits still face significant challenges and require improvements.

Currently, antioxidant and pro-angiogenic injectable hydrogels are fabricated either by grafting drugs onto polymer backbone or by loading them into the network [12,13]. However, the pre-graft methods commonly require moderate reaction conditions and often suffer from altered bioactivity, limited loading efficiency and suboptimal release profile [14,15]. While additional delivery systems such as micelles, liposomes, and COF/MOF nanomaterials are indispensable for the loading methods to control the release of different drugs in an optimal manner. Despite the growing interests in novel gas therapies (NO, H2S, CO) [16,17] and growth factors (e.g., VEGF, PDGF) [18], their clinical applications are also considerably limited by short half-lives, susceptibility to inactivation, and high costs [19]. As for the restoration of electrical signal propagation, conductive biomaterials have emerged as a promising approach [20]. The integration of a sufficient amount of conductive components, such as metal nanomaterials (MNMs), carbon nanomaterials (CNMs), conductive inorganic nanomaterials (INMs), and conductive polymers (CPs), into the injectable hydrogel matrix still faces several critical problems. MNMs and CPs have very limited biodegradability, posing high biocompatibility risks such as chronic inflammation or immune rejection; while IMNs exhibit rapid degradation in aqueous environments, especially in vivo, leading to premature functional loss [21]. Furthermore, these conductive components possess rigid architectures and have a strong tendency to aggregate, which could easily lead to inhomogeneous electrical and mechanical properties [[22], [23], [24]]. Sophisticated manufacturing technology is necessary to ensure that these conductive components achieve homogeneous dispersion and that hydrogels maintain structural integrity, thus restricting their advanced application.

Therefore, designing a novel biodegradable injectable hydrogel that integrates the aforementioned regenerative traits without relying on multiple bioactive substances and complex delivery systems, while also exhibiting conductivity and being fabricated through a simple and mild method, represents a highly promising yet challenging endeavor. Catechol-containing compounds, belonging to the realm of cuticle chemistry, can form strong coordinate bonds with iron (III) (Fe3+), making them suitable for engineering wet, soft systems with enhanced and dynamic mechanical properties [[25], [26], [27], [28]]. Pyrogallol, a polyphenolic compound characterized by catechol and o-triphenol groups, has emerged as a promising building block for antioxidant biomaterials. Among its derivatives, 2,3,4-trihydroxybenzaldehyde (THA), which contains a phenolic aldehyde group, stands out as a competitive candidate for constructing functional hydrogels using facile methods [[29], [30], [31]]. After coordinating with metal ions, the phenolic aldehyde group enables THA to serve as a bonding motif, while also realizing the efficient loading and controlled release of small bioactive molecules [32]. Conductive oligomers exhibit enhanced solubility, excellent biocompatibility, and electroactive behavior comparable to those of their corresponding CPs [33]. Biodegradable biomaterials with conductivity and stable mechanical properties can be readily prepared by grafting conductive oligomers onto non-conductive polymers [6].

Inspired by the aforementioned concerns, we proposed a novel injectable hydrogel (AT-g-GA/AHA/THA@Fe/Arg) through a simple strategy that can modulate excessive ROS, enhance electrical conduction and promote angiogenesis for the treatment of MI. The hydrogel was fabricated by combining aniline tetramer (AT) grafting gelatin (GA) (AT-g-GA), adipic dihydrazide-modified hyaluronic acid (AHA), THA and ferric iron coordination compound (THA@Fe), and L-arginine (Arg) (Fig. 1A). Firstly, the main network of the hydrogel, composed of hyaluronic acid (HA) and GA, endowed the injectable hydrogel with ECM-like physicochemical and biological properties, thereby facilitating cell adhesion and growth [34]. Grating aniline tetramer onto GA ensured that the hydrogel had conductivity [35], while THA and Arg imparted the hydrogels with antioxidant and pro-angiogenesis capabilities [30,36], respectively. Secondly, THA@Fe served as the crosslinker and established the hydrogel networks through dynamic Schiff base and coordinate bonding [37], which enhanced the hydrogel with injectable and adaptive yet stable mechanical properties for continuous diastolic-systolic conditions (Fig. 1B). Simultaneously, Arg could be loaded through a dual mechanism, utilizing both dynamic covalent grafting and physical mixing, consequently exhibiting a sustained release profile. Such a strategy overcomes the limitations of traditional permanent covalent grafting method or solely physical mixing for drug loading, which commonly lead to unsuitable release profiles [[38], [39], [40]]. Moreover, the presence of catechol, o-triphenol, and phenolic aldehyde groups in THA@Fe endowed the hydrogel with tissue adhesiveness, enhancing substance exchange and signal communication [41]. To evaluate the therapeutic potential of this multifunctional injectable hydrogel, the physicochemical properties including gelation time, injectability, stiffness, viscoelasticity, self-healing capability, and biocompatibility were first optimized. Subsequently, the regenerative capabilities of ROS scavenging, conductivity, and enhancement of endothelial cell tube formation and migration were evaluated in vitro. Eventually, by employing a rat MI model, the optimized injectable hydrogel was evaluated for its therapeutic effects on in vivo MI healing, focusing on comprehensive aspects including the MI microenvironment, the structural and functional improvements of infarcted hearts. Collectively, the results demonstrated that our novel facile strategy is effective in developing a multifunctional injectable hydrogel which could modulate the MI repair process through synergistic effects (Fig. 1C).