Food contamination and spoilage caused by pathogenic microorganisms pose significant challenges to the food industry. To address these issues, antimicrobial food packaging has emerged as a critical solution for enhancing food safety by preventing microbial contamination and inhibiting foodborne pathogens, thereby indirectly extending shelf life. This approach integrates antimicrobial agents into biomaterials to inhibit microbial growth through controlled release, direct contact, and barrier formation. In this context, biomaterials primarily serve as structural platforms, whereas antimicrobial agents are the primary contributors to microbial inactivation. Recent advancements have shifted packaging trends from conventional plastics to active, biodegradable, and edible biopolymer films. Both natural biomaterials (e.g., polysaccharides and proteins) and synthetic biomaterials (e.g., polymeric materials such as PLA and PVA) are employed in these systems. The need for antimicrobial food packaging has, therefore, increased significantly and this packaging is seen as a promising tool for improving the safety of food by inactivating microbial pathogens and controlling microbial growth. These antimicrobial systems can be directly blended or surface coated into polymer matrices, providing targeted antimicrobial properties. However, regulatory and safety challenges remain before widespread commercial application. Migration of active substances must comply with applicable regulatory limits, while the potential toxicity associated with certain antimicrobial agents, including essential oils at high concentrations and nanoparticles, requires careful evaluation. This review comprehensively discusses antimicrobial biomaterials employed in food packaging, its mechanism of action and fabrications methods, primarily for microbial control and food safety. It focuses on the role of antimicrobial agents in these systems and its effect on food safety, not on material development or quality improvements. The review also considers the challenges that are currently facing and proposes future research directions for improving the antimicrobial packaging solutions.
Biomaterials are evolving from passive scaffolds to responsive platforms, yet most lack true feedback regulation. A shift toward adaptive biomaterial systems that integrate sensing, computational processing, and dynamic actuation directly within a macromolecular network could transform these multifunctional biomaterials into precision platforms capable of regulating biological processes in real time.
Antimicrobial resistance (AMR) represents a defining crisis in modern infectious disease medicine. Gram-negative microbes such as carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae are becoming more resistant than ever. Traditional methods of treatment using antibiotics are ineffective because of the presence of several envelope layers, active efflux pumps, and biofilm production. In contrast, bacteriolytic therapy can exacerbate host immunopathology owing to systemic endotoxin release. Host-defense peptides are thus being explored for their ability to kill bacteria, neutralize lipopolysaccharide (LPS), and modulate innate immune responses in a single treatment; however, clinical use remains hindered by their low stability, high binding to serum proteins, and narrow therapeutic index. In this review, we will discuss the use of biomaterial platforms in the design of peptide-based therapeutics to not only increase their efficacy by reducing peptide clearance but also optimize the immunological environment in which these peptides operate. We will discuss the role of various characteristics, such as surface chemistry, mechanical stiffness, and protein corona, in influencing macrophage polarization and downstream signaling pathways. In addition, we point out a significant limitation within this area of research: many preclinical studies continue to use minimum inhibitory concentration and hemolysis values, which fail to account for the host-directed effects that make these approaches significant. For future progress in this realm, new endpoints are required, along with more clinically relevant animal models and a true incorporation of peptide design into biomaterials engineering.
Gout is a complex and progressive inflammatory disease caused by the deposition of monosodium urate (MSU) crystals. Recent research on the application of biomaterials in gout treatment has shown promising potential. Biomaterials, with their unique biocompatibility, controlled release properties, and targeted delivery capabilities, offer significant advantages in enhancing drug solubility and bioavailability, reducing systemic adverse effects, and enabling more precise and stage-specific therapeutic intervention. In this review, we systematically categorize the various biomaterials applied in gout therapy over the past five years, including nano-drug delivery systems, microneedle drug delivery systems, and novel biomaterial-based therapeutics for gout treatment. We highlight the design principles, construction strategies, and mechanisms of action associated with each type of biomaterial. By comparatively analyzing the functions of different biomaterial platforms, this review further summarizes their potential therapeutic roles, relative advantages, and current limitations in gout management. In addition, we discuss currently used gout-related animal models and their relevance to preclinical evaluation, and synthesize emerging therapeutic targets that may guide future biomaterial design. Overall, this review highlights both the opportunities and the translational challenges of biomaterial-based strategies for gout therapy, providing insights for the development of more targeted, effective, and clinically relevant therapeutic approaches. 1. This review describes the main animal models used in gout research and compares the advantages and disadvantages of different methods. 2. It summarizes the major types of biomaterials being investigated for gout treatment and the principles behind their design. 3. It explains how these biomaterials are prepared, how they work in the body, and what therapeutic effects they have shown in experimental studies. 4. It also highlights potential therapeutic targets and future directions for the application of biomaterials in gout treatment.
Soft biomaterials strongly influence cellular behavior by transmitting mechanical cues via well-characterized mechanotransduction pathways. However, translating insights from simplified in vitro systems to complex in vivo responses remains a challenge. This review provides a framework for assessing the translational relevance of mechanobiological studies across different scales-from single cells and organoids to tissues and organs. First, we categorize soft biomaterials based on their architecture and mechanical features to establish consistent terminology. We then investigate how cells interpret the transmitted mechanical signals in advanced in vitro systems that simulate physiologically relevant mechanical environments. To discuss the translational potential, we present a scoring system and a comparative analysis demonstrating that physiological specificity, rather than experimental complexity, determines predictive value. Simple systems can yield highly translatable outcomes when mechanical cues mimic native conditions, while advanced models require careful validation to ensure their relevance. By integrating biomechanics, electrophysiology, and systems biology, we outline principles and validation strategies that enhance the predictive utility of mechanobiological findings and ultimately support the design of more effective biomaterials and tissue-engineered systems.
Natural polyphenols have garnered significant attention in pharmaceuticals, food, and cosmetics due to their unique bioactive functions such as antioxidant, anti-inflammatory, antitumor, and antibacterial properties. The multiple phenolic hydroxyl groups in polyphenol molecules (catechol and galloyl moieties) enable dynamic complexation with various substances through non-covalent interactions, including hydrogen bonding, hydrophobic interactions, electrostatic interactions and coordination bonding. The excellent self-assembly and interfacial properties of polyphenols enable the construction of multiscale and multifunctional delivery systems, ranging from nanoscale to microscale. Microscale delivery systems play an irreplaceable role in disease treatment, and research on polyphenol-based microscale delivery systems is gaining momentum. This review systematically describes various polyphenol-based microscale delivery systems, including coacervate droplets, Pickering emulsions, microcapsules, microparticles, and polyphenol-modified microbes and cells, and discusses their self-assembly mechanisms, preparation methods, functional characteristics and therapeutic applications. Finally, we outline the research advances in polyphenol self-assembled delivery systems and discuss future directions for the development of next-generation polyphenol-based biomaterials.
Successful functional tissue regeneration demands biomaterials that can recapitulate the dynamic structural, mechanical, and biochemical properties of native extracellular matrices (ECMs). Conventional biomaterials fall short in this regard. Biomimetic hydrogels serve as a transformative paradigm rather than simple scaffolds, evolving from structural mimics to actively programmable platforms for cell guidance. This review first dissects the design principles for hydrogels to mimic key ECM features, including biochemical composition, spatiotemporal microenvironment, and tunable mechanical properties. It then illustrates how these biologically inspired principles contribute to advanced functions such as strong adhesion, self-healing, adaptive lubrication, and intelligent responsiveness. We further discuss how these integrated properties overcome tissue-specific regeneration challenges in osteochondral defects, nerve injuries, and chronic wounds, establishing a function-driven design framework that links material performance to clinical efficacy. Finally, we propose a development roadmap for next-generation intelligent hydrogels. We highlight the importance of constructing systems with closed-loop feedback to enable dynamic adaptation to the changing microenvironment. The translation of such intelligent systems via scalable fabrication and strict validation represents a critical research direction. This review summarizes recent progress and provides a conceptual framework for developing biomimetic hydrogels into interactive therapeutic agents that synergize with tissue regeneration.
Anterior cruciate ligament (ACL) reconstruction conventionally prioritizes immediate mechanical stability; however, it does not fully prevent long-term post-traumatic osteoarthritis, residual neuromuscular deficits, or incomplete biological integration. This limitation reflects the gap between structural graft substitution and true functional regeneration, including insufficient ligament-bone interface healing, delayed graft vascularization and remodeling, loss of proprioceptive afferents, and the demanding intra-articular environment characterized by synovial fluid washout and high cyclic mechanical loading. To bridge this gap between conceptual biomaterials and clinical orthopedic practice, this review critically deconstructs the physiological bottlenecks of current ACL repair and reconstruction and outlines a translational roadmap for next-generation biointelligent ligament grafts. We evaluate emerging strategies including: (1) cross-scale hierarchical biomaterials designed to mitigate graft-tunnel micromotion, interfacial shear, and tunnel widening; (2) spatially retained and cell-responsive biological release systems that reduce the risk of uncontrolled intra-articular diffusion and ectopic ossification; (3) orthobiologic adjuncts, including platelet-rich plasma and platelet-rich fibrin, as clinically accessible but still insufficiently standardized tools for biological augmentation; (4) piezoelectric and mechanically shielded niches aimed at supporting proprioceptive neuralization; and (5) fluid-stable implantable sensors coupled with data-driven rehabilitation and digital twin concepts. By integrating biomimetic design, immune modulation, sensory restoration, and technology-readiness considerations, this review provides a clinically oriented framework for shifting ACL therapy from passive mechanical replacement toward active neuro-mechanical regeneration.
Dry electrospun nanofibrous facial masks (D-ENFMs) have emerged as a promising platform in nano/biomaterials research, attributed to their eco-friendly nature and convenient use. However, their practical application is significantly hindered by three critical barriers: low active ingredient loading capacity, slow dissolution kinetics, and undesirable solid residues after use. Inspired by the unique "dry-state preservation and wet-state release" survival strategy of Anastatica hierochuntica, a bioinspired core-sheath beaded-structured nanofibrous membrane (B-NFM) is developed via one-step emulsion electrospinning. This architecture enables long-term stable encapsulation of squalane emulsion droplets in the dry state and triggers ultra-fast dissolution upon contact with moisture, followed by efficient moisturization through the synergistic "water locking-hydration replenishment-barrier repair" mechanism of squalane. The surfactant coconut diethanolamide plays a dual critical role: stabilizing the oil-in-water emulsion for efficient squalane encapsulation, and modulating molecular reorganization to impart superhydrophilicity, enabling instantaneous dissolution and complete residue elimination. Notably, this one-step strategy is successfully scaled to a 256-needle roll-to-roll electrospinning system, achieving a daily output of 155.52 m2. This bioinspired design paradigm will pave the way for a new generation of sustainable, high-performance nanomaterials for advanced skincare applications.
Whitlockite (WH), a magnesium-bearing calcium phosphate biomineral, is the second most abundant inorganic component in human bone tissue after hydroxyapatite, and is emerging as a next-generation bone repair material. This review systematically summarizes the research progress of WH in bone tissue engineering, providing a comprehensive overview from fundamental physicochemical properties to cutting-edge biomaterial applications. We first elucidate the unique rhombohedral crystal structure of WH and its functional basis as a reservoir of bioactive ions (Mg2+, Zn2+, Sr2+, etc.), and clarify its regulatory mechanisms in the three key biological processes of osteogenesis, angiogenesis, and neurogenesis. On this basis, we systematically compare the advantages and limitations of three synthesis strategies-precipitation, hydrothermal, and solid-state reactions-in terms of phase purity, crystallinity, scalability, and particle morphology control. Furthermore, we explore four application forms of WH in bone defect repair: bioactive coatings for orthopaedic implants to enhance osseointegration, 3D porous scaffolds that support vascular infiltration, injectable composites that adapt to complex defect geometries, and piezoelectric materials that convert physiological mechanical stimuli into in situ electrical signals to accelerate osteogenesis by leveraging WH's intrinsic piezoelectricity. Finally, we analyze the key challenges in translating WH from laboratory research to clinical practice, and the future directions, including 4D-printed smart scaffolds, ion-coded neuro-vascular-osteogenic coupling, and wireless self-powered piezoelectric regenerative systems. Collectively, these multidimensional attributes of WH offer new insights for the rational design of smart biomaterials that dynamically regulate the regenerative microenvironment and achieve holistic functional bone restoration.
DNA hydrogels are widely explored in biomedical research for their programmability and soft tissue-mimicking mechanics. However, their application in load-bearing implants is restricted by insufficient mechanical robustness, especially for mimicking the biomechanics of the nucleus pulposus, which is a naturally occurring functional tissue essential for spinal flexibility and shock absorption in the intervertebral disk. Here, we report a novel single-pot, two-step fabrication strategy in which long DNA strands produced by rolling circle amplification form an initial viscoelastic network that is subsequently reinforced through controlled thermal self-assembly of proteins, physically stapling the DNA chains into a mechanically tunable hybrid matrix. This synergistic protein reinforcement enables precise control over the morphological and mechanical properties of DNA hydrogels while improving stability under enzymatic and pH stress. The reinforced hydrogels maintain structural integrity under complex deformation and sustained compression in ex vivo nucleus pulposus models and exhibit pressure-dependent drug release. Overall, this study establishes protein reinforcement within viscoelastic gel networks as a distinct materials design strategy for creating programmable biomaterials that integrate molecular precision with mechanical resilience for use in mechanically demanding biological environments.
Proximal humeral fracture is one of the most prevalent osteoporotic fractures in the elderly, ranking third after hip and distal radius fractures and accounting for approximately 10% of all geriatric fractures. With population aging, its global incidence continues to rise annually. Most mild and stable fractures can be managed conservatively, while nearly 15%-20% of displaced complex fractures require surgical intervention. Current mainstream strategies include locking plate fixation, intramedullary nailing, hemiarthroplasty, anatomic total shoulder arthroplasty, and reverse total shoulder arthroplasty. Owing to poor bone quality and multiple comorbidities in elderly patients, individualized treatment based on fracture classification, medial calcar integrity and functional demands is essential. This review systematically summarizes the clinical application, biomechanical characteristics, functional outcomes and complications of mainstream treatments for elderly proximal humeral fractures. Latest advances in fracture classification, medial calcar reconstruction, biological augmentation, intelligent surgical technology and degradable biomaterials are elaborated. Meanwhile, the limitations of existing studies and future research directions are clarified, aiming to provide evidence-based references for clinical individualized diagnosis and treatment of senile osteoporotic proximal humeral fractures.
Post-stent implantation vascular complications, primarily characterized by impaired re-endothelialization and persistent inflammatory responses, frequently result in delayed vascular healing and subsequent adverse clinical outcomes, including late-stage thrombosis and in-stent restenosis. Cytokines act as master regulators of vascular repair, coordinating endothelial regeneration, inflammatory responses, and tissue remodeling. Angiopoietin-1 (Ang-1) is a particularly significant regulatory molecule within the vascular system, exerting pleiotropic effects on vascular homeostasis through dual regulation of endothelial regeneration and vascular stabilization. Self-assembling peptide systems, with their unique combination of programmable molecular design and inherent biocompatibility, are revolutionizing targeted vascular therapy development. In this study, we developed an RADA16 peptide-based coating loaded with Ang-1 to mimic the unbound state of endogenous Ang-1, thereby modulating inflammatory responses, promoting re-endothelialization, and accelerating vascular repair. The RADA16 peptide coating enabled sustained Ang-1 release for more than 14 days. Both the peptide coating and Ang-1-loaded peptide coatings exhibited excellent cytocompatibility. The Ang-1 loaded coating significantly enhanced the growth and migration of human umbilical vein endothelial cells (HUVECs) while selectively inhibiting the proliferation of smooth muscle cells (SMCs). Furthermore, the coating effectively suppressed macrophage (MA) proliferation and reduced secretion of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Meanwhile, both PAs coating and PAs-Ang coating promote the polarization of macrophages toward the M2 phenotype, facilitating inflammation resolution and tissue repair. The Ang-1 loaded coating exerting anti-inflammatory effects and creating an immune-favorable microenvironment conducive to vascular repair. The Ang-1-eluting peptide coating exhibited a trifecta of therapeutic effects by selectively promoting endothelial cell proliferation and migration while suppressing inflammatory responses. This multifunctional bioactive coating reveals anti-inflammatory activity, pro-endothelialization capacity, and inhibition of smooth muscle cell hyperplasia. This work offers a novel strategy for cardiovascular biomaterials development, and provides a new surface modification approach for cardiovascular implants.
Electrospun silk fibroin nanofibers (SFNFs) combine exceptional biocompatibility, tunable mechanical properties, and a native extracellular matrix (ECM)-mimetic architecture, making them compelling scaffolds for tissue engineering. Despite rapid progress, current research often pursues isolated material enhancements, lacking a cohesive strategy that aligns scaffold design with the complex biophysical and biochemical microenvironments of targeted tissues. To bridge this gap, this review presents a "design-application coupling" framework that systematically integrates SFNF composition, processing, and surface modifications with tissue-specific regenerative demands. Rather than exhaustively detailing basic manufacturing, we concisely distill advanced electrospinning modalities and targeted functionalization strategies─such as inorganic reinforcement and immunomodulation─that dictate mechanical robustness and bioactivity. Crucially, we map these engineered properties directly to their emerging clinical applications, comprehensively analyzing SFNF performance in the regeneration of bone, skeletal muscle, cardiovascular, neural, and skin tissues. Finally, we discuss critical challenges to clinical translation, including scalability and regulatory standardization, and propose future directions toward smart, bioresponsive materials. This framework provides a systematic pathway from bench-side innovation to bedside application, guiding the next generation of SFNF-based regenerative scaffolds.
Understanding the internal architecture of hydrogel materials is essential for their effective use in biomedical and pharmaceutical applications, yet the use of noninvasive, spatially resolved methods remains limited. We report a robust analytical approach using spatially resolved pulsed-field gradient nuclear magnetic resonance (PFG-NMR) spectroscopy to quantify the depth-dependent self-diffusion of small molecular probes in intact hydrogel systems. By introducing probes post-gelation via passive downward diffusion, this method avoids perturbations associated with probe incorporation during gel formation and enables nondestructive profiling of internal gel architecture. Applied to high amylose maize starch, agarose, and calcium-triggered low-molecular-weight (LMWG) gels, the technique revealed vertical variations in network density and porosity in starch gels, corroborated by scanning electron microscopy, while the other gels exhibited uniform structure. In contrast, conventional nonselective PFG-NMR yields a single self-diffusion coefficient averaged over the entire sample and is unable to reveal the heterogeneity present. Our methodology broadens the NMR analytical toolkit for characterizing soft matter systems and offers promising utility in evaluating structurally complex biomaterials, where spatial heterogeneity is functionally relevant.
Fetuin-A is a plasma protein of interest for bone-interfacing applications because of its role in mineralization processes through calcium/phosphate ion-binding capabilities. However, the role of fetuin A in the initial stages of cellular interaction with biomaterials and the mechanisms involved are not fully clear. This work investigated the response of osteoblast-like Saos-2 cells to model gold substrates presenting preadsorbed fetuin-A as a surface modification to determine the role of the protein in cell attachment and proliferation. Correlative quartz crystal microbalance with dissipation (QCM-D), surface plasmon resonance, and radiolabeling confirmed that fetuin-A adsorbed on model surfaces in similar quantities compared to serum albumin but formed a less packed layer with increased water entrapment. Cells attached to gold surfaces presenting preadsorbed fetuin-A displayed morphological characteristics similar to those with preadsorbed albumin with lower average surface area and maximum axis compared to the fibronectin control. Over 3 days, fetuin-A exhibited lower cellular proliferation compared to the fibronectin control, likely correlated to the decrease in cellular metabolism observed at the same time point, and persisted over 7 days. These results provide insight into the role of adsorbed fetuin-A for bone-interfacing implant applications, suggesting that the preadsorption of the protein alone is not sufficient to promote early stages of osseointegration.
Based on the profound consistencies in structural composition, physiological functions, and pathological responses, we defined the stomach, esophagus, intestines, bladder, urethra, uterus, and vagina as 'Muscular Organs' for the first time. Current repair strategies for muscular organ defects predominantly emphasize structural reconstruction while often neglecting functional restoration; thus, the introduction of this concept aims to explore novel biomaterial design strategies for their repair. This review systematically elucidates the anatomical homologies, shared pathological mechanisms, and regenerative bottlenecks of muscular organs. Regarding regenerative solutions, we highlight biomimetic design principles primarily driven by structural mimicry and supplemented by functional modifications, alongside the application of advanced manufacturing technologies in constructing these biomaterials. Furthermore, we prospectively discuss the breakthrough potential of cutting-edge technologies. Ultimately, we hope that this concept proposal will provide novel perspectives on material design for muscular organ repair and promote the broader application of biomimetic strategies in this field.
Hydrogels combining the biochemical complexity of the native extracellular matrix (ECM) with the tunable properties of protein-based biomaterials are promising for neural tissue engineering. In this study, decellularized spinal cord meninges (dSCM) were combined with water-soluble hydrophilic silk fibroin (hSF) and enzymatically crosslinked using a horseradish peroxidase/H2O2 system to develop composite hydrogels. A detergent-free, sonication-assisted decellularization method effectively removed cellular components while preserving matrix integrity, reducing residual double-stranded DNA to below 50 ng mg-1 dry weight and retaining key ECM constituents, including collagen and glycosaminoglycans. Hydrogels prepared at different dSCM:hSF ratios showed composition-dependent structural and mechanical behavior, with the 1:0.5 and 1:1 formulations exhibiting the most favorable compressive stiffness and viscoelastic performance. Structural, thermal, and morphological analyses further indicated that hSF incorporation improved matrix stability and contributed to more controlled swelling and degradation behavior. Biological evaluation showed that the 1:0.5 formulation promoted neovascularization in the chorioallantoic membrane assay without evident adverse inflammatory response. In addition, SH-SY5Y cells maintained high viability and showed increased expression of the neuronal-associated markers β-III tubulin and MAP2 over time. Overall, these findings suggest that dSCM:hSF hydrogels provide a promising platform for neural tissue engineering.
To overcome the trade-off between the low viscosity required for printability and the high mechanical strength required for functionality in dental resins for vat photopolymerization 3D printing by developing a hydrogen-bond engineering strategy. Three dental oligomers (Bis-GMA, UDMA, and Bis-EMA) were blended with four diluents differing in hydrogen-bonding ability. Fourier transform infrared (FTIR) spectroscopy, rheometry, three-point bending tests and 3D printing performance tests were carried out to evaluate hydrogen bond formation, viscosity, mechanical properties, printability and accuracy. FTIR and rheological tests confirmed strong hydrogen bonding between MAA and matrix oligomers. The optimized formulation, n(MAA): n(UDMA) = 2:1, achieved flexural strengths of 228 MPa (mold-filled) and 178 MPa (3D-printed) and elastic modulus of 5.3 GPa and 4.0 GPa, respectively, whereas the viscosity was only 307 mPa·s-a dramatic improvement over that of neat UDMA (viscosity 9689 mPa·s, mold-filled mechanical strength 174 MPa and 3.8 GPa). The hydrogen-bonding diluents also demonstrated significant advantages in composite resin formulations. Hydrogen bond engineering decouples viscosity from mechanical strength, enabling the fabrication of low-viscosity, high-strength dental resins for 3D printing. This scalable platform overcomes the longstanding viscosity-strength trade-off, offering promising potential for dentistry and other fields of photocurable additive manufacturing.
Small-conductance Ca2+-activated potassium channels (SK) are increasingly investigated as therapeutic targets for atrial fibrillation. Emerging evidence, however, indicates their functional relevance in ventricular pathologies. This study investigates the expression, localization, and functional role of SK2 and SK3 channel subtypes in ventricular myocardium from patients with and without valvular disease-associated remodeling. Human ventricular tissue was obtained from 125 patients undergoing cardiac surgery. mRNA levels of KCNN2 and KCNN3 were quantified with RT-qPCR. Protein levels and localization of SK2 and SK3 were analyzed via immunohistochemistry. Functional responses were evaluated by optical mapping of living ventricular myocardial slices. Gene expression was not significantly altered in remodeled myocardium. SK2 and SK3 were located in striated patterns, colocalizing with L-type Ca2+ channels in all patients. SK3 was also present at intercalated discs, although this pattern was significantly reduced in remodeled myocardium. Functionally, SK channels were inactive in non-remodeled myocardium, with neither apamin nor SKA-31 altering action potential duration (APD). In contrast, in remodeled myocardium, apamin prolonged and SKA-31 shortened APD. This response to SKA-31 was more pronounced in patients with reduced ejection fraction. Mechanistically, SKA-31 effects were abolished by L-type Ca2+ channel blockade or CaMKII inhibition, but not by PKA inhibition, suggesting that SK activation is Ca2+ and CaMKII-dependent. SK channels become functionally upregulated in the early stages of ventricular remodeling despite the absence of gene expression changes. SK activation might rely on post-translational modifications and calcium handling alterations. These findings highlight the need for caution in targeting SK channels therapeutically.