Mechano-immunomodulatory biomaterials: From immune mechanosensing to translational design

Abstract

Mechanical cues are increasingly recognized as active regulators of immune-cell behavior rather than passive properties of tissues or biomaterials. In mechano-immunology, matrix stiffness, viscoelasticity, topography, shear stress, tensile strain, compression, and interstitial fluid pressure are understood to shape macrophage polarization, dendritic-cell maturation, neutrophil trafficking, T-cell activation, and tissue repair through coordinated mechanosensing and mechanotransduction. Yet immune responses to mechanical cues remain highly context-dependent, making simplified rules such as “stiff matrices promote inflammation” or “soft matrices promote repair” difficult to generalize across material systems, dimensionalities, ligand-presentation profiles, immune-cell sources, and activation states. Key bottlenecks include reconstructing multidimensional in vivo mechanical microenvironments, standardizing mechanical characterization and reporting, resolving immune-cell heterogeneity, and bridging reductionist platforms with clinically deployable biomaterials. Here, we summarize how immune cells decode mechanical signals through membrane-proximal mechanosensors, cytoskeletal remodeling, nuclear mechanotransduction, epigenetic regulation, and mechano-metabolic coupling. We then discuss how biomaterial parameters, including stiffness, viscoelasticity, mechanical stimulation, surface topography, degradation, and mechano-responsive delivery, can be engineered to modulate immunity in tissue regeneration, drug delivery, and theranostics. Finally, we highlight how artificial intelligence (AI)-enabled biophysical modeling and multimodal data integration may define context-specific mechanical design windows and accelerate next-generation mechano-immunomodulatory biomaterials.

Graphical abstract

Highlights

• •Mechanical cues are framed as design signals for immunomodulatory biomaterials.
• •Mechano-immunomodulatory biomaterials drive regeneration, drug delivery, and theranostics.
• •AI and digital twin systems accelerate personalized biomaterial design.

1. Introduction

Tissue homeostasis depends on molecular signals and the physical architecture of the extracellular matrix (ECM) in equal measure, a duality that pathogens, malignancies, and fibrotic diseases exploit by remodeling the mechanical microenvironment to suppress immune surveillance. Innate immune and adaptive immune cells are highly sensitive to biophysical stimuli, including shear stress, tensile strain, compressive loads, and interstitial fluid pressure (IFP) [1,2]. Convergent evidence now establishes that mechanical forces profoundly shape the migration, activation, and functional plasticity of immune cells [3]. This convergence defines the field of mechano-immunology, which maps the bidirectional crosstalk between physical force and immune regulation across length scales from single-receptor conformational changes to tissue-level remodeling. For instance, macrophages, dendritic cells, and T cells exhibit divergent phenotypic and functional behaviors in response to varying substrate stiffness, cyclic strain, and physical confinement [[4], [5], [6]]. Importantly, macrophage responses to stiffness extend beyond the simplistic “stiff-M1/soft-M2” paradigm and are instead highly context-dependent, being regulated by factors such as material platform, cell species, dimensionality (2D or 3D), and ligand presentation profiles [4,5]. In this review, M1 and M2 are used as heuristic shorthand for macrophage polarization while recognizing that macrophage activation in vivo exists along a dynamic continuum rather than as a strict binary state. Accordingly, functional descriptors such as M1-like/pro-inflammatory, M2-like/pro-regenerative are used preferentially to facilitate comparison with the biomaterials literature without implying fixed polarization states [7]. Similarly, dendritic cell adhesion and antigen presentation are influenced by substrate compliance [8], whereas T cells dynamically modulate receptor triggering and effector functions according to the mechanical resistance encountered at the immunological synapse [9]. Collectively, these mechanically driven functional adaptations critically shape the progression of tissue inflammation and repair, highlighting the central role of physical cues in mechano-immunomodulation.

The conceptual foundation of mechano-immunology has emerged from converging advances in mechanobiology, immunology, and biomaterials. Early mechanobiology studies established that cells sense substrate rigidity and translate extracellular mechanical resistance into changes in adhesion, cytoskeletal organization, and cell fate [2,10,11]. The discovery of Piezo1 and Piezo2 as mechanically activated ion channels, together with the identification of YAP/TAZ as mechanosensitive transcriptional regulators, provided molecular frameworks for linking physical forces to biochemical and transcriptional outputs [[12], [13], [14]]. In parallel, immunology studies revealed immune-cell activation, migration, antigen recognition, and intercellular communication as intrinsically force-dependent processes [3,9]. These insights shifted biomaterial design from passive structural support toward active regulation of host responses through stiffness, viscoelasticity, topography, degradation, and mechanically responsive delivery. Recent work further shows that mechanical cues regulate macrophage polarization, dendritic-cell maturation, T-cell cytotoxicity, innate immune activation, foreign body responses, and tumor immunosurveillance [[15], [16], [17], [18], [19], [20], [21]]. Accordingly, the field is moving from single-parameter mechanical modulation toward multidimensional, context-specific, and data-guided design of mechano-immunomodulatory biomaterials.

Despite substantial advances in immunotherapy and regenerative medicine, mechanical cues remain an underappreciated parameter in biomaterial design. Conventional strategies have primarily relied on biochemical interventions, including cytokines and growth factors, while mechanical regulation has generally been considered secondary [22,23]. However, pathological microenvironments are almost invariably accompanied by mechanical dysregulation. In chronic inflammation, persistent ECM remodeling, edema, disrupted interstitial fluid transport, and repetitive mechanical loading sustain immune-cell recruitment and inflammatory activation. In fibrosis, progressive collagen deposition, enzymatic crosslinking, and matrix stiffening create mechanically persistent niches that reinforce fibroblast activation and macrophage-mediated remodeling. In tumors, matrix stiffening, solid stress, dense ECM architecture, and elevated interstitial fluid pressure limit drug penetration, restrict CD8⁺ T-cell infiltration, and promote immunosuppressive macrophage phenotypes [1,[24], [25], [26], [27], [28], [29], [30], [31]]. However, conventional biomaterials are typically designed based on static mechanical matching, surface chemistry, degradation kinetics, or biochemical factor delivery, and therefore rarely capture the multidimensional, dynamic, and spatially heterogeneous mechanics of diseased tissues [16,19,20,32,33]. This mismatch poses a central mechanistic challenge: immune outcomes observed in vitro are difficult to assign to any single parameter because stiffness, viscoelasticity, topography, confinement, fluid pressure, inflammatory cytokines, and cell-state heterogeneity are tightly coupled in vivo. Thus, pathological mechanics establish the biological rationale, the limitations of conventional materials define the engineering gap, and the difficulty of mechanistic deconvolution highlights the methodological challenge driving the development of mechano-immunomodulatory biomaterials.

Mechanistic understanding of mechano-immune coupling has catalyzed a reorientation in biomaterial design: rather than relying exclusively on bioactive molecular coatings, physical parameters of the material itself are now deployed as primary immune-regulatory inputs. Deliberate adjustment of stiffness and viscoelasticity can reprogram macrophage polarization states and reshape their secretory profiles [15,34,35]. Our previous work demonstrated that hydrogel substrates with a stiffness of 80 kPa could significantly attenuate inflammation in skin and bone tissues through the inhibition of Piezo1-mediated mechanotransduction [36]. In parallel, micro- and nano-topographical scaffolds have been developed to regulate dendritic cell maturation, antigen cross-presentation, and subsequent T-cell recruitment [37,38]. In the context of T-cell biology, mechanosensing and microfluidic platforms have emerged as indispensable tools for quantifying the interplay among mechanical force, cellular deformation, and effector function, thereby guiding the rational optimization of mechanical parameters [39]. Beyond passive scaffolding, mechano-responsive materials that release immunomodulatory payloads in response to defined physical triggers enable spatiotemporally gated therapeutic interventions [40,41]. Collectively, these strategies constitute the methodological foundation of “mechano-immunomodulation,” offering transformative opportunities to enhance immunotherapy, mitigate chronic inflammation, and promote tissue regeneration.

Numerous studies have established tissue mechanotransduction as a key regulator of immunity, disease progression, and therapeutic responses [[1], [2], [3]]. Building on this foundation, this review shifts the focus from mechanotransduction as a general disease-regulatory mechanism to mechanosensitive biomaterials, with the aim of translating principles of mechanosensation into actionable biomaterial design strategies. Specifically, this review is organized into three integrated sections: (i) immune-cell mechanosensing and mechanical signal decoding, which establish the mechanistic basis of mechano-immunology; (ii) translation of these mechanisms into biomaterial design, including quantitative and semi-quantitative design windows and application-oriented strategies; and (iii) material-specific translational barriers and AI-enabled biomaterial design workflows (Fig. 1). This biomaterial-centered framework aims to bridge mechanistic mechano-immunology with practical material engineering and translational design.

Fig. 1.

Conceptual overview of mechano-immunomodulation.

2. Interactions between the immune system and biomaterials

2.1. Immune responses induced by biomaterials

Upon implantation, biomaterials engage plasma proteins, complement components, and pattern-recognition receptors within seconds, initiating a staged inflammatory response whose amplitude and resolution trajectory are critically determined by material surface properties [32,33]. This process is initiated by the rapid adsorption of proteins onto the material surface, resulting in the formation of a protein corona. The adsorbed protein layer alters the physicochemical properties of the biomaterial surface while simultaneously providing critical signals for subsequent immune-cell recognition and adhesion. Concurrently, activation of the complement system generates chemokines and inflammatory mediators that recruit neutrophils and monocytes to the implantation site, thereby initiating the acute inflammatory response. When biomaterials exhibit favorable biocompatibility, this inflammatory response is typically resolved within several days. In contrast, poor host compatibility may lead to persistent inflammation, fibrotic encapsulation, and ultimately functional failure of the implant. Therefore, understanding and modulating the early immune response is essential for improving the long-term performance and therapeutic efficacy of biomaterials.

2.2. Immune cell responses to biomaterials

2.2.1. Functions of neutrophils in early immune responses

As the first immune cells recruited to biomaterial implantation sites, neutrophils play indispensable roles in acute inflammatory responses. They contribute to pathogen clearance and early biomaterial surface remodeling through the release of cytotoxic mediators, including reactive oxygen species (ROS), proteases, and antimicrobial peptides [42,43]. In addition, activated neutrophils secrete a broad range of inflammatory mediators that amplify local inflammatory signaling and recruit additional immune cells [44]. Recent studies have demonstrated that, beyond their classical antimicrobial functions, neutrophils also participate in immune regulation through the formation of neutrophil extracellular traps (NETs) [45]. These networks of DNA and protein structures serve to entrap invading pathogens while simultaneously regulating subsequent macrophage recruitment and function, thereby promoting the resolution of inflammation and the progression toward tissue repair. Conversely, impaired neutrophil clearance or sustained neutrophil activation is frequently associated with chronic inflammation and fibrotic progression.

2.2.2. Roles of macrophage polarization at the material-host interface

Macrophages, as central effectors of the innate immune system, play pivotal roles at the biomaterial-host interface. Macrophage functional states span a continuum of activation phenotypes regulated by the microenvironmental context. The heuristic M1 (classically activated, pro-inflammatory) and M2 (alternatively activated, tissue-reparative) designations capture the poles of this spectrum but do not reflect the full diversity of intermediate states encountered at biomaterial interfaces [7]. The pro-inflammatory macrophages contribute to the clearance of foreign materials and pathogens through the secretion of cytokines, including TNF-α, IL-1β, IL-6, and ROS. However, excessive pro-inflammatory activation may also induce tissue damage and sustained inflammation [46]. In contrast, pro-regenerative macrophages secrete anti-inflammatory mediators, such as IL-10 and TGF-β, together with ECM remodeling enzymes that promote tissue repair and regeneration. Importantly, biomaterial surface chemistry, matrix stiffness, and topographical characteristics can all influence macrophage polarization states. Consequently, the rational engineering of biomaterial properties to direct favorable macrophage phenotypic responses has emerged as a central strategy in contemporary biomaterials design [[15], [16], [17],47].

2.2.3. Adaptive immune responses of T cells and B cells to biomaterials

Although adaptive immune responses are initiated later than innate immune responses, they play pivotal roles in long-term implantation outcomes and chronic foreign body reactions. Antigen-presenting cells, particularly dendritic cells, recognize and process biomaterial-associated antigens before presenting them to T cells, thereby initiating antigen-specific adaptive immune responses [48,49]. Different activated T-cell subsets, including Th1, Th2, Th17, and regulatory T cells, mediate distinct immunological outcomes. Among these subsets, Th1 and Th17 cells predominantly drive pro-inflammatory responses [50,51], whereas Th2 cells promote anti-inflammatory activities and fibrosis [52], and Treg cells contribute to the establishment of immune tolerance [53]. B cells can produce antibodies against biomaterial-associated antigens, thereby enhancing opsonization, material clearance, or fibrotic encapsulation [54]. The establishment of immunological memory compounds this concern: antigen-specific T and B cells formed against biomaterial-associated determinants may mount amplified secondary responses upon re-exposure to the same or antigenically related materials [55]. Therefore, the design of next-generation biomaterials should minimize immunogenicity while simultaneously promoting immune tolerance to optimize long-term implant performance and host integration.

2.3. Material interface properties governing immune responses

2.3.1. Surface chemistry

The surface chemistry of biomaterials plays a critical role in regulating immune-cell behavior. Parameters such as surface charge [56,57], hydrophilicity [58,59], functional groups [60], chemical bonding characteristics [61,62], and surface energy [63,64] can influence immune-cell recognition and activation by altering the composition, abundance, and conformation of adsorbed proteins. In general, highly positively charged surfaces tend to enhance cell adhesion and immune activation, although they may also exacerbate inflammatory responses [65]. In contrast, neutral or mildly negatively charged surfaces are generally more favorable for reducing nonspecific protein adsorption, protein denaturation, and excessive inflammation. Importantly, the immunomodulatory effects of specific functional groups are highly dependent on the material system. For example, in certain biomaterial platforms, polar functional groups such as hydroxyl and carboxyl groups may promote pro-regenerative macrophage responses by increasing surface hydrophilicity and modulating the adsorbed protein corona. However, this phenomenon should not be generalized as a universal principle applicable to all biomaterials [66]. In addition, antifouling surface modifications based on polyethylene glycol (PEG), phosphorylcholine, or polysaccharides can effectively reduce protein adsorption and cellular adhesion, thereby mitigating undesirable immune activation [67,68]. In our previous work, precise regulation of macrophage-mediated immune responses, together with enhanced antibacterial activity, was achieved through the grafting of different doses of phase-transitioned lysozyme onto the surface of sodium titanate nanowires [69]. These findings further suggest that surface functionalization using integrin-binding peptides, anti-inflammatory molecules, or immunomodulatory ligands may represent a promising strategy for achieving more precise regulation of interfacial immune responses.

2.3.2. Surface topography

Biomaterial surface topography can modulate immune-cell behavior across nano-, micro-, and macroscale dimensions. Nanoscale ordered architectures can influence macrophage adhesion, spreading, and polarization. However, these effects are jointly determined by feature size, structural regularity, and surface chemistry, and ordered topographies are not invariably associated with the induction of M2 polarization [70]. Microscale topographical features regulate immune-cell functions by modulating cell morphology, cytoskeletal organization, and adhesion patterns. For instance, cell elongation induced by micro-grooved surfaces is frequently associated with attenuated pro-inflammatory phenotypes [71]. At the macroscale, porosity, pore size, and pore interconnectivity can affect immune-cell infiltration, nutrient diffusion, and vascularization potential, although these effects are likewise dependent on material composition and mechanical properties [72,73]. Notably, different immune-cell populations may exhibit distinct responses to identical topographical features. Therefore, surface topography should be considered a probabilistic and directional regulator of immune responses rather than an isolated deterministic factor [74,75].

2.3.3. Mechanical properties

The mechanical properties of biomaterials, particularly matrix stiffness, viscoelasticity, and stress-relaxation behavior, exert profound influences on immune-cell function through mechanotransduction pathways. In general, immune cells can sense alterations in matrix stiffness and subsequently modulate their adhesion, migration, and cytokine secretion profiles. However, the oversimplified paradigm that softer matrices promote M2 polarization whereas stiffer matrices favor M1 polarization is not universally applicable, as immune responses are jointly regulated by the material system, the dimensionality of the microenvironment, ligand-presentation characteristics, and the activation state of immune cells [76,77]. For example, studies using different hydrogel systems have shown that softer matrices or substrates with faster stress-relaxation kinetics may favor reparative immune responses, whereas other reports suggest that moderate stiffness or dynamically increasing stiffness within defined mechanical windows can also promote M2-like or pro-regenerative programs [77,78]. These mechanosensitive responses are closely associated with the integrin-cytoskeleton-YAP/TAZ axis and NF-κB signaling pathways [12,79]. Furthermore, dynamic mechanical stimuli, including cyclic stretching, compression, and shear stress, further diversify the mechanisms through which biomaterials regulate immune-cell behavior [18]. Therefore, the immunological effects of implanted biomaterials cannot be assessed solely on the basis of elastic modulus. Additional factors, including viscoelasticity, stress-relaxation kinetics, and in vivo mechanical loading history, must also be comprehensively considered.

2.3.4. Biodegradation

The biodegradation characteristics of biomaterials directly shape the local immune microenvironment [80]. Degradation kinetics, the physicochemical properties of degradation products, and their release profiles collectively determine the extent of immune-cell recruitment and activation [[81], [82], [83], [84], [85]]. Biomaterials that degrade excessively rapidly may provoke intense acute inflammatory responses, whereas slowly degrading materials are more likely to induce persistent low-grade inflammation. Regarding degradation byproducts, acidic degradation products may exacerbate inflammatory reactions, while certain polypeptides and polysaccharides possess intrinsic immunomodulatory activities [86]. In addition, the dynamic evolution of material surface properties during degradation further influences immune cell-biomaterial interactions. Studies have demonstrated that rationally engineered degradation profiles can promote beneficial sequential immune responses characterized by an initial moderate pro-inflammatory phase followed by a reparative immune response. More recently, stimuli-responsive degradable biomaterials, such as enzyme-responsive polymers sensitive to inflammatory microenvironments, have further expanded the potential applications of biodegradation-mediated immune regulation [87,88]. These materials can dynamically modulate their degradation behavior according to local immune conditions, thereby enabling adaptive immune regulation. Overall, precise control over biomaterial degradation kinetics has become a central challenge in modern biomaterials engineering, particularly in regenerative medicine applications where implanted materials are ultimately expected to be replaced by host tissues.

3. Mechanosensing and mechanotransduction in immune regulation

3.1. Mechanical cues and immune cell responses

Mechano-immunology is an interdisciplinary field that combines mechanobiology and immunology to elucidate how mechanical cues regulate immune-cell functions and influence disease pathogenesis as well as therapeutic outcomes. Immune cells reside within highly dynamic mechanical microenvironments and continuously sense and respond to diverse biophysical stimuli, including tissue stiffness, shear stress, and ECM mechanics [[89], [90], [91]]. Recent studies have demonstrated that mechanical factors exert broad regulatory effects on immune cells. Beyond influencing fundamental immune-cell functions, they also modulate cellular activation, migration, and inflammatory responses through alterations in membrane receptor organization, cytoskeletal assembly [92], and downstream signaling pathways, thereby shaping immune defense and tissue repair processes [19,20]. For example, changes in tissue stiffness can modulate macrophage phenotypes, whereas hemodynamic shear stress regulates neutrophil rolling, adhesion, and trans-endothelial migration. By employing advanced biomimetic platforms that recapitulate physiological mechanical microenvironments, researchers have begun to elucidate the roles of mechanical signaling in immune regulation during fibrosis, atherosclerosis, cancer, and other pathological conditions [25].

Immune-cell responses to mechanical cues are primarily characterized by two closely interconnected processes, namely migration and functional polarization. Immune-cell migration is not governed solely by chemotactic signaling. Rather, migrating cells continuously sense matrix stiffness, adhesive properties, and spatial confinement, and subsequently adjust their migratory dynamics and migration modes accordingly. For example, neutrophils can exhibit biphasic migratory responses to substrate stiffness, whereas macrophages may alter their migration behaviors under excessively stiff or highly confined conditions [5,93]. At the molecular level, mechanical stimuli regulate leading-edge protrusion formation and trailing-edge contraction through the activation of small GTPases such as Rac1 and RhoA, thereby influencing the efficiency of directional migration [94]. In addition, Piezo1-mediated Ca²⁺ transients further drive cytoskeletal remodeling, enabling immune cells to traverse narrow endothelial junctions and dense interstitial spaces during trafficking to inflammatory or tumor sites [95].

Mechanical cues also directly regulate immune-cell effector programs and functional polarization. In macrophages, stiffness-dependent polarization has been observed across multiple experimental systems. However, the specific mechanical thresholds and phenotypic outcomes remain highly model-dependent. Stiffer matrices preferentially promote pro-inflammatory programs, whereas other reports suggest that dynamically stiffening substrates or matrices with intermediate stiffness can induce pro-regenerative phenotypes [76,96]. These effects are frequently associated with signaling pathways involving YAP/TAZ, Piezo1, and NF-κB [[96], [97], [98]]. T-cell activation is similarly influenced by the mechanical microenvironment. Specifically, the stiffness and mechanical loading modes of antigen-presenting interfaces can alter T-cell receptor (TCR) triggering efficiency, force persistence, and immunological synapse organization, thereby modulating activation thresholds and downstream functional outputs [9,99,100]. Furthermore, matrix topography can indirectly shape immunological outcomes by altering contact patterns between immune cells and target cells, as well as among immune cells themselves, thereby influencing the efficiency of intercellular signaling.

During antigen recognition, B cells encounter membrane-bound or material-presented antigens with distinct mechanical and structural properties, including stiffness, mobility, and surface geometry. Antigen-tethered polyacrylamide gels demonstrated that B-cell activation is highly sensitive to substrate stiffness within the kilopascal range, with stiffer substrates promoting BCR, phospho-Syk, and phosphotyrosine accumulation at the immunological synapse and increasing CD69 expression [101]. This stiffness discrimination is mediated by PKCβ-dependent FAK activation and is further enhanced by the adhesion molecules ICAM-1 and VCAM-1 [102]. Moreover, nanotopographic surfaces regulate B-cell actin dynamics and signaling, with nanoridge spacing controlling ventral actin oscillations in a BCR-, actin polymerization-, and myosin contractility-dependent manner [103].

Recent studies have further demonstrated that mechanical and biochemical signals act in a coordinated manner to regulate immune-cell phenotypes during macrophage polarization and related immune processes. For example, the biological effects of IL-4, CSF1, and other cytokines can be contextually reshaped by matrix stiffness, stress-relaxation behavior, and three-dimensional confinement. Consequently, identical cytokine stimuli may induce distinct degrees of reparative or inflammatory programs under different mechanical conditions [21,104,105]. These synergistic interactions indicate that multifunctional biomaterial design cannot rely solely on the simple combination of “mechanical parameters and bioactive molecules.” Instead, biomaterials should be engineered to deliver spatiotemporally coordinated cues tailored to specific immune stages and therapeutic objectives.

Mechano-chemical crosstalk is inherently bidirectional, as biochemical stimulation can reconfigure mechanosensor expression, clustering, and activation thresholds. For example, LPS or IFN-γ priming upregulates Piezo1 expression in macrophages, lowering the mechanical threshold for channel activation [15]. Consequently, subsequent exposure to cyclic hydrostatic pressure or matrix stiffening elicits amplified inflammatory responses, including accelerated NF-κB nuclear translocation and increased IL-6 and TNF-α production. Likewise, LPS and acute inflammatory cytokines enhance the activation and surface abundance of leukocyte integrin αMβ2 (Mac-1/CD11b/CD18), thereby modulating catch-bond formation, traction-force generation, and sensitivity to nanoscale topography [106]. By resetting the cell-intrinsic mechanical set point, biochemical cues determine how immune cells interpret subsequent material-derived mechanical signals, biasing inflammatory or regenerative responses. These findings highlight an important design principle: biomaterials interact with immunologically conditioned rather than naïve immune cells within dynamic pathological microenvironments, making biochemical priming an essential consideration in mechano-immunomodulatory biomaterial design.

Collectively, the mechanisms by which immune cells perceive mechanical cues and the summary of the material design windows are presented in Table 1.

Table 1.

Cell-type-specific mechanosensing mechanisms, functional readouts, and material design considerations for major immune cell populations.

Immune Cell Type	Key Mechanosensors	Primary Mechanical Cues	Functional Readouts	Material Design Windows	Representative References
Macrophages	Piezo1, TRPV4, integrins (αMβ2/Mac-1), YAP/TAZ, Rho/ROCK	Substrate stiffness, cyclic strain, confinement, viscoelasticity	Phenotypic polarization (pro-inflammatory vs. pro-regenerative continuum), cytokine secretion (TNF-α, IL-6, IL-10, TGF-β), phagocytosis, efferocytosis	Stiffness-dependent; context-dependent rather than a universal "stiff-M1/soft-M2" rule; stress-relaxation kinetics and dimensionality (2D vs. 3D) critically modulate outcomes	[5,15,21,96]
Dendritic Cells	Piezo1, integrins, podosomes, actin cortex	Substrate stiffness, surface topography, confinement	Maturation marker expression (CD83, CD86, MHC-II), cytokine production (IL-12, TGF-β1), CCR7 expression and migratory competence, antigen cross-presentation, T cell priming efficiency	Stiff substrates (≈50 kPa) enhance pro-inflammatory cytokine secretion (IL-12) via Piezo1-Ca2+-SIRT1-HIF-1α; DC cortical stiffness increases upon maturation to enhance T cell priming	[8,107,108]
T Cells	TCR (catch-bond mechanosensor), Piezo1, LFA-1 (αLβ2), cytoskeleton	Substrate/APC stiffness, mechanical force at immunological synapse (pN-scale), shear stress	TCR triggering efficiency, activation thresholds (biphasic response), cytotoxic force generation, effector cytokine production (IFN-γ), proliferation	Biphasic stiffness response for activation; optimal activation at intermediate stiffness; TCRs transmit defined pN forces for antigen discrimination; CTLs use mechanical force to potentiate perforin-mediated killing	[6,9,99,100]
B Cells	BCR (mechanical force sensor), integrins (LFA-1, VLA-4), FAK, PKCβ	Substrate stiffness, mechanical force at immune synapse	BCR microclustering and polarization, antigen extraction force, spreading and adhesion, affinity discrimination in germinal centers	Stiff substrates enhance BCR signaling and accumulation at immune synapse via PKCβ–FAK axis; germinal center B cells use specialized biomechanical pulling forces for affinity-based antigen extraction	[102,109,110]
Neutrophils	Piezo1, TRPV4, GEF-H1/RhoA/ROCK, selectin catch-bonds	Shear stress, substrate stiffness, confinement during transmigration	NETosis (shear-induced via Piezo1-Ca2+-calpain), bactericidal activity (Nox4 upregulation via HIF-1α), pro-angiogenic reprogramming, rolling and adhesion	Shear stress magnitude critically regulates NETosis; Piezo1-mediated Ca2+ influx during trans-endothelial migration activates bactericidal programs; biphasic migration response to substrate stiffness	[89,95,111]
Microglia	Piezo1, TRPV4, YAP/TAZ, integrins	Tissue/matrix stiffness, Aβ fibril stiffness	Clustering and phagocytosis of Aβ plaques, pro-inflammatory activation, morphological transformation, cytokine release	Ultra-soft neural tissue environment (0.1–1 kPa); Piezo1 senses Aβ fibril stiffness to drive microglial clustering and plaque compaction; stiffness-dependent activation is modulated by inflammatory context	[[112], [113], [114]]

A methodological understanding of mechano-immunology is essential for translating mechanical concepts into testable biomaterial design principles. Current platforms can be grouped into three complementary categories: mechanical characterization, force manipulation, and biomimetic reconstruction. Mechanical characterization techniques, including atomic force microscopy (AFM), AFM-based single-cell force spectroscopy, and traction force microscopy, quantify cell and tissue stiffness, immune-cell adhesion, receptor–ligand mechanics, and traction forces during T-cell activation, immunological synapse formation, and cytoskeletal force generation [[115], [116], [117]]. Force-manipulation tools, such as optical and magnetic tweezers, apply or measure pico-to nano-newton forces on receptors, membrane tethers, intracellular structures, or ligand-coated beads, enabling direct interrogation of immune mechanosensing and force-dependent signaling [118,119]. Biomimetic platforms, including microfluidic systems and organ-on-a-chip devices, recreate shear stress, confinement, pressure gradients, and multicellular architectures to model neutrophil migration, T-cell deformability, tumor–immune interactions, vascular inflammation, and immune-competent pathological niches [39,120]. Together, these platforms should be selected according to the mechanical question, immune-cell type, and physiological loading mode.

3.2. Membrane-proximal mechanosensors: integrins and mechanosensitive ion channels

Immune-cell mechanosensing begins at the membrane-proximal interface, where extracellular mechanical cues are converted into intracellular biochemical signals through adhesion receptors, mechanosensitive ion channels, and receptor-associated force-sensing complexes. Among these molecular systems, integrins and mechanosensitive ion channels represent two major classes of mechanosensors that enable immune cells to detect matrix stiffness, ligand resistance, shear stress, osmotic pressure, membrane tension, and physical confinement [13,14,18,121,122]. Integrins, a family of transmembrane receptor proteins, are among the principal mechanosensors through which immune cells detect ECM mechanics [121]. Immune cells express multiple integrin heterodimers, including αLβ2 (LFA-1), α4β1 (VLA-4), and αMβ2 (Mac-1), whose activation states are tightly regulated through conformational changes [123,124]. Upon engaging ECM ligands such as fibronectin, collagen, and laminin, integrins transition from low-to high-affinity conformational states, initiating canonical outside-in and inside-out signaling. Intracellular integrin domains then nucleate focal adhesion complexes through recruitment of adaptor proteins including talin, kindlin, and α-actinin, to assemble mechanosensitive focal adhesion complexes that couple extracellular mechanical stimuli to FAK/Src signaling, Rho GTPase activation, and downstream cytoskeletal remodeling pathways [121,125]. Distinct immune-cell subsets exhibit differential responses to integrin-mediated mechanical signaling. For example, the sensitivity of T cells to substrate stiffness and mechanical loading modalities is closely associated with their activation states and differentiation programs [99,126]. In addition, integrins mediate mechanical communication between immune cells through the regulation of immunological synapse formation, thereby critically influencing the functional interactions between T cells and antigen-presenting cells [[127], [128], [129]].

Mechanosensitive ion channels are critical molecular sensors that enable immune cells to perceive mechanical stimuli and convert physical signals into ion fluxes and downstream biochemical events [13,14,18,122]. Among these channels, Piezo1 and members of the TRPV/TRPM channel families are among the most extensively investigated in immune regulation [130,131]. Piezo1 is a nonselective cation channel that responds to changes in membrane tension and regulates Ca²⁺ influx, cytoskeletal organization, and inflammatory mediator secretion [15,18]. Emerging evidence indicates that matrix stiffness can modulate Piezo1-dependent mechanosensitive responses in macrophages, thereby influencing inflammatory and reparative phenotypes [15,96]. In addition, TLR4 signaling engages Piezo1 to activate the Ca²⁺–CaMKII–Mst1/2–Rac axis, thereby enhancing macrophage phagocytosis, mitochondrial-phagosomal ROS production, and bacterial clearance [132]. Piezo1 also regulates immune-cell trafficking by mediating mechanosensing during neutrophil transendothelial migration, inducing Ca²⁺ signaling and enhancing bactericidal activity [95]. Piezo2 is a mechanically activated cation channel highly sensitive to indentation, stretch, touch, proprioception, and inflammatory mechanical pain [13,14,122,133]. Emerging evidence further implicates Piezo2 in tumor immunity. Tumor cell-intrinsic Piezo2 suppresses the IRF-1/IL-15 axis after radiotherapy, impairing CD8⁺ T-cell stemness and antitumor immunity [134]. Thus, Piezo2 is emerging as a mechanosensitive regulator linking tissue mechanics, neuroimmune signaling, and antitumor immunity, although its direct roles in macrophages, dendritic cells, T cells, and B cells remain to be validated. Channels such as TRPV4 participate in Ca²⁺-dependent signaling triggered by shear stress, osmotic pressure, and tissue swelling, and are involved in the regulation of inflammatory responses in myeloid cells, barrier integrity, and immune-cell interactions [135,136]. Notably, TRPV4 preferentially responds to low-intensity shear stress and osmotic alterations and has been implicated in regulating dendritic-cell antigen presentation and T-cell activation. Importantly, the expression patterns and biological functions of mechanosensitive ion channels vary among immune-cell subsets, thereby providing opportunities for cell-type-specific therapeutic targeting. Meanwhile, inflammatory microenvironments can reciprocally modulate the expression and sensitivity of mechanosensitive ion channels, establishing a complex feedback network that integrates mechanical and biochemical signaling pathways [19,137]. Unlike Piezo and TRPV4, TRPM7 functions as a channel-kinase that integrates divalent cation influx with kinase-dependent signaling. TRPM7-mediated Ca²⁺ influx is required for LPS-induced macrophage activation, TLR4 endocytosis, IRF3 activation, and NF-κB nuclear translocation [138]. In biomaterial-associated macrophage responses, TRPM7 also mediates Mg²⁺-dependent immunomodulation. During early bone repair, Mg²⁺ upregulates TRPM7 and enhances Mg²⁺ influx in monocyte–macrophage lineage cells, promoting nuclear accumulation of TRPM7-cleaved kinase fragments and histone H3 phosphorylation at inflammatory cytokine promoters [139]. However, prolonged Mg²⁺ exposure may overactivate NF-κB signaling and impair late-stage bone maturation, highlighting the temporal dependence of TRPM7-mediated immune regulation and the need for precise control in degradable magnesium-based biomaterials [139].

Importantly, integrins and mechanosensitive ion channels function as interconnected rather than independent mechanosensing systems. Integrin engagement modulates membrane tension, cytoskeletal prestress, and receptor organization, thereby influencing ion-channel activation, whereas ion-channel-mediated Ca²⁺ influx regulates actin remodeling, adhesion-complex maturation, and immune-cell migration. This membrane-proximal crosstalk enables immune cells to integrate multiple mechanical cues, including stiffness, ligand density, shear stress, confinement, and inflammatory stimulation. Accordingly, biomaterial design should treat adhesion-ligand presentation and mechanosensitive ion-channel activation as coupled, rather than independent, design parameters.

3.3. Cytoskeletal remodeling and mechanical signal amplification

The cytoskeletal network serves as the structural framework of immune cells while simultaneously functioning as a central platform for mechanotransduction and signal amplification [92]. In immune cells, actin filaments, microtubules, and intermediate filaments collectively participate in the sensing, transmission, and amplification of mechanical cues. The actomyosin contractile system generates intracellular tension and drives dynamic morphological changes. Accordingly, variations in matrix stiffness are frequently accompanied by alterations in actin polymerization and myosin activity, thereby modulating mechanotransductive signaling outputs [15]. Microtubules primarily regulate immunological synapse formation, cell polarization, and vesicular transport, while their stability is itself sensitive to mechanical conditions [140]. Intermediate filaments are mechanically coupled to the nuclear envelope and chromatin architecture, thereby contributing to the transmission of mechanical signals to the nucleus [141,142]. Importantly, these three cytoskeletal systems operate in a highly coordinated manner and collectively form an integrated mechanical network through crosslinking proteins such as plectin and filamin, thereby enabling synchronized cellular responses to external mechanical stimuli. Previous studies have demonstrated that intracellular prestress states and geometric constraints jointly determine cellular mechanosensitivity. Moreover, anisotropic topographical features, such as microgrooved surfaces, can induce cytoskeletal reorientation, thereby altering force-transmission efficiency and ultimately influencing downstream immune-cell behavior [143,144].

The Rho GTPase family and its downstream effector ROCK function as critical molecular switches linking mechanical stimulation to cytoskeletal remodeling [145,146]. In immune cells, RhoA, Rac1, and Cdc42 respectively regulate stress-fiber contraction, leading-edge protrusion formation, and cell polarization. Adhesion-mediated mechanical signaling, alterations in cell morphology, and ion-channel activation can modulate Rho GTPase activity through GEF/GAP regulatory networks, thereby influencing immune-cell migration, phagocytosis, and inflammatory phenotypes [[147], [148], [149], [150], [151], [152], [153]]. Importantly, Rho/ROCK signaling exhibits pronounced spatiotemporal dependence, and its immunological effects are jointly shaped by cell morphology, duration of mechanical loading, and inflammatory context. Consequently, this pathway is more appropriately regarded as a central signaling hub integrating mechanical and inflammatory cues, rather than as a simplistic unidirectional “pro-inflammatory switch” [71,148,154].

Together, cytoskeletal remodeling links membrane-proximal mechanosensing to nuclear mechanotransduction. By integrating signals from integrins, mechanosensitive ion channels, substrate geometry, and mechanical loading, the cytoskeleton amplifies external mechanical cues to coordinate migration, adhesion, phagocytosis, antigen presentation, cytokine production, and transcriptional regulation. Accordingly, cytoskeletal organization should be considered a central intermediary linking material mechanics to immune-cell function in mechano-immunomodulatory biomaterial design.

3.4. Nuclear mechanotransduction and transcriptional regulation

After mechanical cues are sensed at the cell membrane and transmitted through the cytoskeleton, they are further converted into transcriptional and epigenetic programs within the nucleus. This nuclear mechanotransduction process links extracellular matrix stiffness, cell spreading, cytoskeletal tension, nuclear deformation, and chromatin organization to immune-cell activation and functional adaptation. YAP/TAZ are central mechanosensitive transcriptional coactivators that function as pivotal regulators of immune-cell mechanotransduction [155,156] (Fig. 2). Within the canonical Hippo signaling pathway, activation of MST1/2 and LATS1/2 kinases promotes YAP/TAZ phosphorylation, cytoplasmic sequestration, and degradation. In contrast, increased mechanical tension, enhanced cell adhesion, and cytoskeletal remodeling are generally associated with Hippo pathway inhibition and the nuclear translocation of YAP/TAZ, and this upstream mechanotransductive process has been consistently supported across multiple cell types [156,157]. Building upon this framework, the downstream immune phenotypes associated with YAP/TAZ nuclear localization are further modulated by environmental factors, including the material system, inflammatory context, cell origin, and experimental endpoints, rather than being linearly determined by nuclear activity alone [21,158]. Accordingly, YAP/TAZ are more accurately interpreted as mediators involved in the decoding of stiffness- and deformation-associated mechanical cues in macrophages. The ultimate induction of pro-inflammatory or reparative programs depends on the specific immune microenvironment in which nuclear translocation occurs, rather than representing an inevitable transition toward a fixed polarization state. Recent advances in mechano-epigenetics further suggest that YAP/TAZ may contribute to long-term epigenetic remodeling. However, the existence of persistent “mechanical memory” in immune cells still requires more direct experimental validation [159].

Fig. 2.

Schematic overview of mechanotransduction in immune regulation.

Classical inflammatory signaling pathways are also modulated by biomechanical contexts, although the available evidence remains heterogeneous across different cell types and experimental models. Existing studies have demonstrated that cytoskeletal tension, adhesion-complex assembly, and ion channel-mediated Ca²⁺ influx can influence both the magnitude and duration of NF-κB and MAPK activation, thereby reshaping inflammatory cytokine-expression profiles [15,19,160]. Accordingly, rather than interpreting stiff matrices as inevitably activating NF-κB/MAPK signaling, a more accurate perspective is that mechanical states modulate the activation thresholds and signaling dynamics of these classical inflammatory pathways through the reorganization of receptor clustering, endocytosis, cytoskeletal prestress, and nuclear transport processes [19,138,160].

Wnt/β-catenin signaling, which has recently emerged as an important mechanosensitive pathway, participates in mechanotransductive responses across multiple cell types, although mechanistic evidence in immune cells is still being progressively established [161]. Current studies suggest that mechanical stimuli may regulate β-catenin stability and nuclear translocation by influencing cell-cell junctions, cytoskeletal tension, and the stability of GSK-3β-associated complexes, while simultaneously engaging in crosstalk with NF-κB, STAT3, and YAP/TAZ signaling pathways. Consequently, Wnt/β-catenin signaling represents an important candidate node within the mechano-immunological regulatory network. Nevertheless, its context-dependent effects across distinct immune-cell populations still require further direct causal investigation.

Accumulating evidence indicates that immune-cell responses to external mechanical cues, including matrix stiffness, topographical features, and mechanical forces, extend beyond transient signaling events and may further induce epigenetic remodeling through the integrated “membrane-cytoskeleton-nucleus” axis, thereby establishing more persistent alterations in gene-expression programs. Extracellular mechanical stimuli are initially transmitted through integrin-mediated adhesion complexes and cytoskeletal tension networks. Subsequently, these mechanical signals are conveyed to the nucleus through the cytoskeleton and the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, composed of nesprin-SUN proteins, resulting in alterations in nuclear lamina organization (e.g., lamin A/C assembly) and chromatin remodeling processes, including histone acetylation and methylation [162]. Recent studies have demonstrated that macrophages within 3D microenvironments achieve mechanosensing through cytoskeletal dynamics and integrate biochemical cues such as CSF1 to regulate chromatin accessibility, thereby driving mechanosensitive gene-expression programs associated with tissue repair [21].

Notably, these epigenetic alterations exhibit a certain degree of persistence. Even after immune cells transition to new mechanical environments, specific epigenetic modifications may remain stable for extended periods [163,164]. Mechanical microenvironments may therefore couple mechanical priming with stabilized chromatin states, thereby contributing to persistent functional bias in immune cells during chronic inflammation. Nevertheless, more direct causal evidence is still required to determine whether genuine mechanobiological memory exists in immune cells, as well as to define its temporal persistence and reversibility.

The LINC (Linker of nucleoskeleton and cytoskeleton) complex serves as a structural bridge connecting the cytoplasmic cytoskeleton to the nucleoskeleton and plays indispensable roles in transmitting mechanical signals to the nucleus. The LINC complex is primarily composed of SUN-domain proteins located at the inner nuclear membrane and KASH-domain proteins localized to the outer nuclear membrane, which interact across the perinuclear space to establish a stable mechanical linkage [165]. In immune cells, the LINC complex forms a continuous mechanical coupling network with the cytoplasmic cytoskeleton, nuclear lamina, and chromatin, thereby enabling the direct transmission of extracellular mechanical forces into the nucleus. Studies have demonstrated that, under inflammatory stimulation, SUN1/2 proteins function as mechanotransductive regulators capable of remodeling nuclear architecture and chromatin organization, thereby promoting M1 macrophage polarization [34]. Mechanistically, the LINC complex regulates the nucleocytoplasmic transport efficiency of transcription factors such as YAP/TAZ and NF-κB by modulating nuclear membrane tension and nuclear pore complex conformation. Simultaneously, it also influences chromatin organization and gene-expression programs through lamin A/C-dependent mechanisms [166,167].

In summary, the representative mechanical sensing signal pathways are summarized in Table 2.

Table 2.

Comparative summary of core mechanotransduction signaling pathways in immune cells.

Mechanosensing pathway/module	Major mechanical inputs or parameters	Main immune-cell types	Key readouts	Representative models or contexts	Strength of evidence and design implication	Reference
Integrin–talin/kindlin–FAK/Src adhesion signaling	Substrate stiffness, ligand density, ligand spacing, ECM tethering, nanoscale topography, adhesive resistance	Macrophages, DCs, T cells, monocytes	FAK/Src phosphorylation, focal adhesion assembly, actin remodeling, spreading, migration, cytokine secretion, antigen presentation	ECM-coated hydrogels, fibronectin/collagen substrates, implant surfaces, immunological synapse models	High to moderate. Strong mechanistic basis, but immune outcome depends on ligand presentation, 2D/3D geometry, and inflammatory context.	[99,105,[121], [122], [123], [124], [125], [126], [127], [128], [129]]
Piezo1-mediated mechanosensitive Ca2+ influx	Membrane tension, matrix stiffness, cyclic stretch, compression, confinement, transendothelial migration	Macrophages, neutrophils, DCs, T cells	Ca2+ transients, Piezo1 activation/inhibition, phagocytosis, cytokine secretion, migration, M1/M2-associated markers	Stiffness-controlled macrophage culture, cyclic-force innate immune models, neutrophil transmigration, mechanically loaded tissues	High. Causal studies using genetic or pharmacological perturbation support Piezo1 as a key immune mechanosensor. Biomaterial design should consider both matrix stiffness and dynamic force exposure.	[[13], [14], [15],18,95,96,100,122]
TRPV/TRPM channel-associated mechanotransduction	Shear stress, osmotic pressure, tissue swelling, membrane stretch, inflammatory microenvironment	Macrophages, myeloid cells, dendritic cells, barrier-associated immune cells	Ca2+ influx, MAPK/NF-κB activation, TLR endocytosis, cytokine expression, antigen presentation	Shear- or osmotic-stress models, inflammatory tissue models, infection or autoimmune-related models	Moderate. Mechanistic evidence is growing, but channel subtype-, tissue-, and disease-specific effects remain incompletely resolved.	[96,130,131,[135], [136], [137], [138],160]
RhoA/Rac1/Cdc42–ROCK cytoskeletal signaling	Cell shape, matrix stiffness, tensile strain, topographical anisotropy, confinement	Macrophages, neutrophils, T cells	Actomyosin contractility, stress-fiber organization, leading-edge protrusion, migration mode, phagocytosis, cytokine profile	Micropatterned surfaces, microgrooved scaffolds, stretch models, confined migration systems	High to moderate. Central hub linking mechanical state to immune function, but effects are strongly time- and context-dependent.	[71,94,[145], [146], [147], [148], [149], [150], [151], [152], [153], [154],160]
YAP/TAZ mechanotransduction	Matrix stiffness, cell spreading, stress relaxation, cytoskeletal tension, nuclear deformation	Macrophages, stromal-immune interfaces, osteoimmune microenvironments	YAP/TAZ nuclear localization, TEAD-target genes, inflammatory cytokines, macrophage polarization, chromatin accessibility	Stiffness-controlled hydrogels, 3D macrophage culture, tissue repair and fibrosis-related models	Moderate. Mechanistic evidence is substantial, but YAP/TAZ activation does not map linearly to either pro-inflammatory or reparative phenotypes.	[21,[155], [156], [157], [158], [159]]
NF-κB/MAPK mechanomodulation	Cytoskeletal prestress, adhesion-complex assembly, ion-channel-mediated Ca2+ influx, stiffness, stretch, topography	Macrophages, dendritic cells, neutrophils	p65 nuclear translocation, IκB degradation, ERK/JNK/p38 phosphorylation, IL-1β, TNF-α, IL-6	LPS-stimulated macrophages on substrates with different stiffness or topography, infection/inflammation models	Moderate. Mechanical cues primarily tune activation thresholds and signaling dynamics rather than acting as deterministic inflammatory switches.	[15,19,76,138,160]
LINC complex–nuclear lamina–chromatin axis	Nuclear compression, substrate stiffness, spatial confinement, cytoskeletal force transmission	Macrophages and other deformable immune cells	Nuclear size and stiffness, SUN1/2 expression, lamin A/C organization, chromatin accessibility, histone modifications, mechanical memory	3D microenvironments, inflammatory macrophage models, nuclear mechanotransduction studies	Emerging to moderate. Mechanistic studies suggest nuclear mechanics contributes to immune programming, but persistent mechanical memory in immune cells requires further validation.	[34,[162], [163], [164], [165], [166], [167]]
TCR and immunological synapse mechanosensing	Antigen-presenting interface stiffness, molecular tension, receptor-ligand mechanical resistance, shear force	T cells, antigen-presenting cells	TCR-pMHC force, CD69/CD25 expression, IL-2 secretion, cytotoxicity, synapse organization	DNA tension probes, stiffness-controlled antigen-presenting substrates, microfluidic T cell assays	High for T-cell mechanosensing; moderate for direct translation into biomaterial-based immunotherapies.	[6,9,99,100,[126], [127], [128], [129]]

Pathway crosstalk is a central feature of immune-cell mechanotransduction. Integrin/FAK signaling, Rho/ROCK-dependent cytoskeletal tension, mechanosensitive ion channels, YAP/TAZ nuclear translocation, NF-κB/MAPK and Wnt/β-catenin signaling, and LINC-mediated nuclear force transmission operate as an interconnected regulatory network rather than isolated linear cascades. Integrin engagement activates RhoA/ROCK signaling to enhance actomyosin contractility and cytoskeletal prestress, thereby promoting YAP/TAZ nuclear localization and modulating receptor clustering, Ca²⁺ influx, and inflammatory signaling thresholds. Conversely, inflammatory cues can remodel cytoskeletal organization and alter mechanosensitivity. Beyond transient signaling, these coupled pathways converge on mechano-epigenetic regulation, whereby cytoskeleton- and LINC-mediated force transmission reshapes nuclear mechanics and chromatin accessibility, allowing mechanical and biochemical cues to jointly regulate transcriptional programs and immune-cell polarization. Such processes may stabilize specific chromatin states and impose persistent functional bias, providing a potential basis for cellular mechanical memory, although its stability and reversibility in immune cells remain incompletely defined.

3.5. Mechano-metabolic coupling in immune regulation

Mechanical cues regulate immune-cell function not only through receptor signaling, cytoskeletal remodeling, and transcriptional regulation but also through metabolic reprogramming. As immune-cell activation, migration, phagocytosis, antigen presentation, cytokine secretion, and tissue repair depend on distinct metabolic programs, changes in tissue stiffness, confinement, stretch, and shear stress reshape immune responses by modulating glycolysis, oxidative phosphorylation (OXPHOS), mitochondrial dynamics, lipid metabolism, and amino acid metabolism [19,168]. Thus, mechano-metabolic coupling constitutes a key mechanistic link between material mechanics and immune-cell fate.

Glycolytic remodeling is a major metabolic consequence of immune mechanotransduction. In dendritic cells, increased substrate stiffness enhances activation, cytokine production, proliferation, and glycolytic flux through TAZ- and Ca²⁺-dependent signaling, linking mechanical stimulation to metabolic priming and adaptive immune activation [108]. In macrophages, Piezo1 drives aerobic glycolysis and LPS-induced inflammatory cytokine production, whereas Piezo1 deficiency suppresses glycolytic activity and attenuates inflammatory responses [169]. Similarly, TRPV4 promotes stiffness-dependent glycolysis by enhancing GLUT1-mediated glucose uptake, thereby facilitating LPS-induced phagolysosome maturation and host defense [170]. Collectively, these findings establish mechanosensitive ion channels as key regulators of immune metabolism, coupling mechanical cues to metabolic reprogramming rather than merely mediating Ca²⁺ influx.

Mechanical cues also regulate mitochondrial metabolism and oxidative phosphorylation. In tumor-infiltrating regulatory T cells, matrix stiffness activates YAP, which enhances mitochondrial OXPHOS by upregulating Lars2, thereby supporting mitochondrial protein translation and immunosuppressive Treg function in stiff tumor microenvironments [171]. In macrophage-associated osteoimmune niches, mechanical tension reshapes mitochondrial dynamics by promoting Drp1-mediated mitochondrial fission and mitochondrial transfer from macrophages to bone marrow mesenchymal stem cells, thereby enhancing osteogenic differentiation and bone formation [172]. Although context dependent, these findings suggest that mitochondria can function as mechanosensitive metabolic hubs that link tissue mechanics to immune-regenerative outcomes.

Lipid metabolism represents an emerging facet of mechano-metabolic regulation. Mechanical cues mediated by YAP/TAZ, cytoskeletal tension, and mitochondrial activity influence lipid biosynthesis, storage, and membrane remodeling, thereby supporting immune-cell activation and differentiation [168]. However, compared with glycolysis and mitochondrial metabolism, direct evidence linking biomaterial mechanics to lipid metabolic reprogramming in immune cells remains scarce. Addressing this gap will require integrated analyses combining mechanical characterization with Seahorse assays, isotope tracing, lipidomics, metabolomics, and single-cell multi-omics to define how stiffness, viscoelasticity, topography, and dynamic loading collectively reshape immune-cell metabolism.

Overall, mechano-metabolic coupling provides a conceptual framework for understanding how biomaterial mechanics durably shape immune-cell fate. Rather than acting solely through transient mechanotransduction, mechanical cues reprogram immune cells by remodeling energy metabolism, biosynthetic flux, mitochondrial organization, and metabolic checkpoints. This perspective suggests that the design of mechano-immunomodulatory biomaterials should be guided by both mechanical parameters and metabolic readouts, including glycolytic activity, mitochondrial respiration, mitochondrial morphology, ROS production, lipid metabolism, and metabolite-dependent epigenetic regulation.

4. Design principles of mechano-immunomodulatory biomaterials

4.1. Regulation of immune responses through matrix stiffness

Matrix stiffness has emerged as a critical design parameter for modulating immune responses in biomaterials engineering. However, accumulating evidence indicates that its effects are neither linear nor monotonic, but instead exhibit pronounced material- and model-dependent characteristics. Multiple studies have demonstrated that softer matrices can promote repair-associated phenotypes in THP-1-derived or primary macrophages [173,174]. In contrast, investigations using specific 3D hydrogel or polyacrylamide systems have reported that lower stiffness may enhance pro-inflammatory programs, whereas intermediate stiffness appears more favorable for pro-regenerative polarization [76,175]. Consequently, it is overly simplistic to regard “high stiffness induces pro-inflammatory” and “low stiffness induces pro-regenerative” as universal principles for biomaterials design. A more accurate interpretation is that matrix stiffness acts cooperatively with ligand density, pore architecture, dimensionality, stress-relaxation behavior, and cell source to collectively shape macrophage phenotypes.

Recent studies have further expanded this design paradigm by incorporating the intrinsic mechanical properties of cells into mechano-immunological engineering strategies. For example, modulation of macrophage membrane cholesterol content and cellular stiffness has been shown to enhance antibacterial activity [176] (Fig. 3a), whereas increased deformability of tumor cells may impair T-cell cytotoxicity and facilitate immune evasion [177] (Fig. 3b). Meanwhile, the pore size and roughness of fibrous scaffolds often synergistically regulate macrophage aggregation and polarization tendencies [178] (Fig. 3c). In addition, engineered high-stiffness cellular backpack systems suggest that stiffness-enhanced inflammatory programs may be strategically exploited for innate immune-cell engineering [179] (Fig. 3d).

Fig. 3.

Stiffness-mediated immune response. (a) Spermidine-functionalized black phosphorus reduces macrophage stiffness and enhances their antibacterial activity [176]. Copyright 2025, Elsevier. (b) Hyperglycemia-induced reduction of tumor cell membrane stiffness promotes immune evasion [177]. Copyright 2026, Elsevier. (c) The SK-structured PCL fibers with nano/micro features regulate macrophage polarization [178]. Reproduced from Ref. [178], © 2023 The Author(s), published by Elsevier Ltd., under the Creative Commons CC BY 4.0 license. (d) Membrane-anchored backpacks with a mechanical stiffness of 50 MPa activate the innate immune response in dendritic cells and macrophages [179]. Copyright 2026, Elsevier.

Importantly, distinct immune-cell populations exhibit differential sensitivity ranges to matrix stiffness rather than universal stiffness-response thresholds. The stiffness sensitivity of dendritic cells, macrophages, T cells, and B cells is highly context dependent, being influenced by receptor loading mode, ligand density, antigen-presentation format, culture dimensionality (2D versus 3D), and cellular activation or differentiation state [8,99,126,180]. Therefore, biomaterial design should prioritize the establishment of application-specific stiffness windows that more closely recapitulate the mechanical properties of physiological tissues relevant to the target immune-cell population, rather than pursuing a single “optimal stiffness value.” Such optimization should further integrate additional parameters, including viscoelasticity, topography, and ligand-presentation characteristics, to achieve more precise and context-dependent immune regulation.

Protein adsorption and fibrotic encapsulation originate at the material surface but are strongly shaped by interfacial mechanics. Matrix stiffness and mechanical mismatch influence protein conformation, cellular traction, macrophage adhesion, fibroblast activation, and collagen deposition. Rigid implants can generate stress concentrations at the tissue–material interface, activating integrin-, cytoskeletal tension-, YAP/TAZ-, and mechanically activated TGF-β-dependent pathways that exacerbate foreign body responses and fibrotic encapsulation [32,33,181]. Conversely, flexible or adhesive interfaces can reduce mechanical discontinuities and suppress fibrotic encapsulation in preclinical implant models [182].

In weight-bearing orthopedic implants, mechanical mismatch also promotes periprosthetic bone resorption through stress shielding. Implants substantially stiffer than the surrounding bone reduce physiological load transfer, leading to localized bone loss and an increased risk of aseptic loosening. Accordingly, low-modulus and functionally graded femoral prostheses, short-stem prostheses, and porous implant architectures have been developed to improve load transfer and mitigate periprosthetic bone loss [183]. These findings highlight that mechanical matching should be optimized not only to achieve structural integration but also to minimize foreign body responses, fibrotic encapsulation, and long-term periprosthetic remodeling.

4.2. Regulation of immune responses via mechanical stimuli

4.2.1. Solid stress

As a distinct biomechanical regulatory factor, solid stress influences immune-cell behavior by altering local strain distribution and force transmission at the material-cell interface. At implantation sites, solid stress may originate from tissue compression, muscle contraction, organ pulsation, and patient movement. Current studies suggest that moderate and controllable cyclic strain can reshape the epigenetic states and cytokine secretion profiles of repair-associated cells, potentially modulating local inflammatory responses through integrins, Piezo1/TRP channels, and cytoskeletal networks. In contrast, excessive or pathological stress is frequently associated with cellular injury, chronic inflammation, and fibrosis [15,18,138,184]. Therefore, within mechano-immunomodulatory biomaterials, stress magnitude, frequency, and duration should be regarded as interconnected design parameters requiring coordinated optimization, rather than as independent mechanical inputs.

Based on the principles of solid stress-mediated immune regulation, a variety of innovative biomaterial platforms have been developed. For example, shape-memory polymers can undergo controllable deformation in response to temperature changes or external stimuli, thereby altering local stress transmission and implant-tissue conformability to provide programmable mechanical conditions for subsequent immune modulation and tissue integration [185,186]. Another representative strategy involves piezoelectric biomaterials, which convert mechanical deformation into localized electrical signals (Fig. 4a), thereby simultaneously influencing inflammatory responses and subsequent regenerative processes in applications such as bone repair [187]. Importantly, the immunomodulatory effects of these materials generally arise from integrated “mechanical-electrical-cellular” coupling, rather than from any single physical parameter acting independently.

Fig. 4.

Mechanically regulated immune response. (a) 3D-printed in situ self-powered scaffolds regulate the immune microenvironment through piezoelectric effects [187]. Copyright 2025, Springer. (b) Reducing tumor interstitial pressure to enhance intratumoral drug delivery and synergistic tumor therapy [188]. Copyright 2022, American Chemical Society. (c) HAB gel dressing with self-negative pressure absorption of exudate and immunomodulatory function [189]. Copyright 2020, Elsevier.

In implant design, stress-shielding effects must also be carefully considered. Conventional rigid implants often reduce physiological stress transfer to surrounding tissues, thereby disrupting local mechanical homeostasis and inducing aberrant immune responses. Consequently, the development of biomaterials with mechanical properties matched to those of adjacent tissues, enabling physiological stress transmission, has become an important strategy for regulating local immune responses and improving long-term implant integration.

4.2.2. Interstitial fluid pressure

IFP is a critical component of tissue fluid mechanics and is closely associated with fluid flow, solute transport, and cellular biomechanical states [1]. During tumor progression, inflammation, and post-implantation tissue remodeling, abnormally elevated IFP can restrict drug penetration, alter immune-cell migration (Fig. 4b), and contribute to the establishment of immunosuppressive microenvironments [188]. Importantly, the absolute magnitude of IFP varies substantially across different tissues and pathological conditions. Therefore, it is inappropriate to extrapolate any fixed pressure threshold as a universal determinant of immune responses. Based on this understanding, researchers have begun developing micro-channelized scaffolds, micro-physiological systems, and osmotic-responsive or fluid-absorbing biomaterials to regulate local fluid distribution and pressure gradients, thereby improving nutrient transport, alleviating the accumulation of inflammatory mediators, and establishing more favorable regenerative microenvironments [189] (Fig. 4c). In oncological contexts, nano-/micro-engineered systems designed to reduce tumor interstitial pressure have been employed to enhance intratumoral drug distribution and synergistic therapeutic efficacy [188]. Consequently, the precise engineering of material pore architecture, permeability, and fluid flux represents an important yet still insufficiently explored direction in the development of mechano-immunomodulatory biomaterials.

4.3. Regulation of immune responses via surface topography

Strategies for regulating immune responses through surface topography are founded on the sensitivity of immune cells to micro-/nanoscale geometric cues. By precisely engineering surface feature size, topographical order, and curvature, biomaterials can selectively modulate cell adhesion, spreading, and phenotypic polarization [144,190]. In terms of feature dimensions, nanoscale structures (10-100 nm) can partially mimic the geometric architecture of the ECM, thereby influencing immune-cell adhesion and polarization tendencies [17]. Emerging evidence suggests that nanoscale, submicron-scale, and microscale surface physical cues, when combined with chemical signaling, exert distinct regulatory effects on macrophages and osteogenic precursor cells. For example, microscale wrinkled structures integrated with chemical signals derived from MXene/HAP coatings can synergistically establish a favorable osteoimmune microenvironment [191] (Fig. 5a). In addition, several studies have demonstrated that specific ordered nano-topographies are more likely to induce repair-associated macrophage responses. However, these effects should be interpreted in conjunction with surface chemistry and material stiffness [194]. Microscale topographical features more directly influence cell morphology, cytoskeletal organization, and local membrane curvature, while regions with high local curvature can alter the activation states of mechanosensitive receptors, thereby regulating downstream signal-transduction pathways [192] (Fig. 5b).

Fig. 5.

Topological regulation of immune response. (a) Micro-/nanocrumpled MXene multilayer coatings accelerate osteogenesis and regulate macrophage polarization [191]. Copyright 2024, American Chemical Society. (b) Silk fibroin film mediates macrophage polarization by regulating macrophage membrane curvature [192]. Copyright 2024, Elsevier. (c) Honeycomb (pore-size)-mediated regulation of macrophage polarization to achieve implant osseointegration [17]. Copyright 2021, American Association for the Advancement of Science. (d) Implant surface topography modulates macrophage inflammatory response [193]. Reproduced from Ref. [193], © 2024 The Author(s), published by Elsevier Ltd., under the Creative Commons CC BY 4.0 license.

Based on these principles, a variety of innovative surface-engineering strategies have been developed. For example, honeycomb-like TiO₂ structures with relatively small feature dimensions (∼90 nm) have been shown to significantly modulate macrophage phenotypes and promote subsequent osteogenic cellular responses [17] (Fig. 5c). Surfaces incorporating gradient microgrooves can guide directional cell migration. However, whether such structures consistently enhance the secretion of specific reparative factors remains dependent on groove dimensions, substrate chemistry, and the surrounding mechanical context [195]. In 3D porous scaffolds, the micro/nanotopography of internal pore walls likewise exerts profound effects on immune-cell behavior. Increasing evidence suggests that moderately rough or wrinkled pore-wall surfaces are more conducive to establishing pro-regenerative microenvironments, whereas smoother surfaces exhibit a greater tendency to induce fibrotic encapsulation [[196], [197], [198]].

The synergistic integration of surface topography and biochemical modification provides expanded opportunities for precision immune modulation [199]. For example, incorporating anti-inflammatory factors such as IL-4 and IL-10 onto ordered microgrooved surfaces, or integrating chemokines and adhesion ligands within nanostructured interfaces, may theoretically enhance the targeted regulation of immune-cell recruitment and phenotypic reprogramming [200]. Furthermore, dynamically tunable surface topographies, including smart adaptive surfaces based on shape-memory polymers or stimuli-responsive hydrogels, can reversibly alter their geometric features in response to local pH, temperature, or other environmental stimuli, thereby establishing a materials-engineering framework for spatiotemporally controlled immune modulation [201].

Surface topography does not act as an isolated regulator: its immunomodulatory outcomes are jointly determined by bulk mechanical properties and surface chemistry, such that identical micro-/nanostructures on substrates of different stiffness can drive distinct or opposing cellular responses [193] (Fig. 5d). Consequently, multidimensional design strategies integrating surface topography, bulk mechanics, and surface chemistry have emerged as a central paradigm in the development of next-generation immunomodulatory biomaterials [202]. Comparative studies demonstrate that topography-mediated immunomodulation cannot be considered in isolation from surface chemistry. TiO₂ honeycomb-like surfaces with comparable anatase composition and hydrophilicity have enabled the effects of feature size on macrophage polarization and osseointegration to be examined under well-controlled chemical conditions [17]. By contrast, identical topographies implemented on chemically distinct substrates, including oxide, polymeric, protein-coated, and mineralized surfaces, present immune cells with different protein adsorption profiles, integrin ligands, surface charges, and hydration states. Thus, surface topography should be viewed as an integral component of the physicochemical interface rather than an independent determinant of immune responses.

To translate these fundamental mechanobiological principles into actionable biomaterial design strategies, we have quantitatively and semi-quantitatively synthesized the established mechanical parameter windows encompassing matrix stiffness, topographical dimensions, and viscoelastic properties that orchestrate the functional outcomes of major immune cell populations (Table 3).

Table 3.

Quantitative and semi-quantitative mechanical design windows for modulating major immune cell populations.

Immune Cell Type	Matrix Stiffness (Elastic Modulus)	Topographical Feature Dimensions	Viscoelasticity & Dynamics	Modulated Functional Outcomes	Reference
Macrophages	Soft-to-Intermediate: Soft (∼1-30 kPa) or specific intermediate (e.g., 80 kPa hydrogels) often favor reparative/M2-like programs and attenuate inflammation.	Nanoscale: ∼90 nm honeycomb structures optimize osseointegration; Microscale: Grooves dynamically induce cellular elongation.	Fast Stress-Relaxation: Rapidly relaxing matrices consistently favor enhanced pro-regenerative signaling compared to slow-relaxing elastic gels.	Phagocytic capacity, directed migration, specific cytokine secretion, and metabolic reprogramming.	[17,35,36,77]
Microglia/Astrocytes	Ultra-Soft (Neural-matched): Highly compliant matrices (∼0.1–1 kPa) matching brain/spinal cord tissue are essential to limit reactive activation.	Aligned Topographies: Nanowire orientation and aligned soft fibers direct microglial migration and limit localized aggregation.	Stress-Relaxing Networks: Compliant viscoelastic properties minimize sustained mechanical stress, reducing secondary inflammatory injury.	Glial scar formation, homeostatic maintenance, neuro-inflammation attenuation, clearance of myelin debris.	[114,203,204]
Dendritic Cells	Wide Range: Modulated by compliance; highly stiff environments (e.g., 50 MPa engineered backpacks) can robustly activate innate immune responses.	Nano/Micro Orders: Virus-like topological surfaces or structured arrays enhance spatial adhesion and antigen uptake.	Osmotic/Fluidic Cues: Highly sensitive to interstitial fluid pressure and low-intensity shear stress via TRPV4 channels.	Antigen cross-presentation, maturation marker expression (CD80/86), T-cell recruitment efficiency.	[8,38,135,179]
T Cells	Stiff Interfaces: Higher stiffness of antigen-presenting interfaces generally lowers TCR activation thresholds.	Spatial Constraints: Micro-confinement limits immunological synapse spreading and alters effector signaling.	Dynamic Load: TCRs function as mechanosensors that distinguish defined pN mechanical resistance forces.	TCR triggering efficiency, targeted cytotoxicity, IL-2 production, synapse stability and duration.	[9,99,100]
B Cells	Antigen-Presenting Interface Stiffness: Stiffer substrates (e.g., >20 kPa) promote stronger BCR signaling and immune synapse formation, while softer substrates favor class switch differentiation.	Antigen Spatial Patterning: Antigen spacing, clustering, and multivalent presentation physically govern BCR signalosome organization.	Mechanical Pulling: B cells exert pN-scale traction forces to extract tethered antigens; extraction efficiency relies on the mechanical resistance of the anchoring surface.	BCR activation threshold, immune synapse formation, antigen extraction (lysosome transport), affinity discrimination.	[101,102,109,110]
Neutrophils	Biphasic: Exhibit biphasic migratory velocity responses corresponding to specific substrate stiffness gradients.	Micro-scale Confinement: Dense ECM architecture/narrow gaps physically trigger morphological leading-edge protrusions.	Shear Stress: Hemodynamic shear stress directly regulates rolling, adhesion, and trans-endothelial migration via Piezo1.	Extracellular trap (NET) release, trans-endothelial migration speed, ROS burst.	[93,95]

5. Biomedical applications of mechano-immunomodulatory biomaterials

5.1. Tissue regeneration

Mechano-immunomodulatory biomaterials reshape tissue regeneration microenvironments through the precise regulation of mechanical properties and immune-cell behavior, thereby demonstrating considerable potential across a wide range of biomedical applications [205] (Fig. 6). These biomaterials serve as structural scaffolds while simultaneously functioning as bioactive platforms that actively regulate immune responses and tissue regeneration. Because immune responses are central regulators of tissue repair, biomaterials can direct the spatiotemporally coordinated activities of macrophages, microglia, and other immune-cell populations by tuning matrix stiffness, viscoelasticity, dynamic mechanical loading, and surface topography [5,206,207]. Through such regulation, these materials promote both structural and functional recovery in bone, skin, cardiovascular, neural, and other tissues [208,209].

Fig. 6.

Application of mechano-immunomodulatory biomaterials in tissue regeneration.

Among these applications, mechano-immunomodulatory biomaterials have achieved particularly significant advances in bone regeneration, largely owing to the close coupling among the immune microenvironment, osteogenic lineage cells, and mechanical stimulation during bone healing. Existing studies consistently demonstrate that scaffold stiffness, nanotopography, degradation behavior, and electromechanical stimulation can all influence macrophage polarization and subsequent osteogenesis. However, no single “optimal modulus” can be universally applied across all material systems [[208], [209], [210]]. Accordingly, a more rational design strategy is to tailor the mechanical and surface properties of biomaterials to establish a pro-regenerative immune microenvironment while simultaneously supporting the osteogenic differentiation of mesenchymal stem cells. In parallel, gradient-stiffness or magnetically graded hydrogel scaffolds have been shown to enhance the chondrogenic and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), thereby improving osteochondral defect repair [211]. Titanium surfaces featuring mesoporous nanocavity architectures, as well as laser-induced micro-/nanostructured titanium alloy implants, have likewise been employed to improve osseointegration through the modulation of macrophage behavior [[212], [213], [214]]. Furthermore, piezoelectric-responsive scaffolds can convert mechanical strain into localized electrical signals, thereby simultaneously promoting osteogenesis and regulating early inflammatory responses to establish a coupled “mechanical-electrical-immune” regenerative microenvironment [215].

In the regeneration of soft tissues such as skin, tendons, and cartilage, biomaterials must simultaneously exhibit relatively low stiffness and high toughness while modulating local immune responses to minimize scar formation and fibrosis [[216], [217], [218]]. In skin regeneration, for example, stimuli-responsive hydrogels have been extensively explored for the treatment of chronic and inflammatory wounds because they can dynamically adjust network architectures and drug-release behaviors in response to changes in temperature, pH, ROS, glucose levels, or enzymatic microenvironments [219,220]. Nevertheless, mechanistic interpretations proposing that a specific thermoresponsive gelatin-hyaluronic acid system remains soft during the inflammatory phase and subsequently stiffens during the proliferative phase, thereby sequentially directing neutrophil/macrophage immune transitions, should be regarded as a design hypothesis rather than an established principle. In tendon repair, scaffolds featuring biomimetic fiber-bundle architectures and aligned surface topographies can recapitulate the hierarchical organization and tensile mechanical properties of native tendons, while simultaneously promoting ordered collagen reconstruction through enhanced immune-matrix interactions [221,222].

Vascular regeneration is likewise highly dependent on the establishment of a favorable immune microenvironment, particularly through the coordinated interplay among monocyte/macrophage polarization, endothelial cell recruitment, and hemodynamic stimulation. Existing studies suggest that compliance-matched small-diameter vascular grafts, together with hierarchically aligned fibrous scaffolds, can regulate macrophage behavior while improving graft patency, thereby optimizing vascular remodeling [[223], [224], [225]]. In addition, cyclic mechanical stimuli generated by pulsatile blood pressure and local fluid flow are believed to influence macrophage cytokine secretion profiles and pro-angiogenic signaling pathways, although the underlying mechanisms and optimal mechanical parameters remain under active investigation [226,227]. Consequently, mechano-immunological design strategies in vascular tissue engineering should not focus exclusively on any single mechanical parameter, but instead should integrate compliance matching, fiber alignment, fluid shear stress, and transmural mass transport into a comprehensive biomaterials design framework.

In the regeneration of the central and peripheral nervous systems, mechano-immunomodulatory biomaterials must mechanically recapitulate the ultra-soft neural microenvironment while finely regulating the responses of microglia, peripheral macrophages, and astrocytes to minimize glial scar formation and secondary injury [203,228]. Central nervous tissues typically exhibit elastic moduli far lower than those of bone and tendon, and this compliant mechanical environment is essential for maintaining neural tissue homeostasis [114,229]. Accordingly, hydrogels such as hyaluronic acid-based systems, whose mechanical properties closely resemble those of brain and spinal cord tissues, have been extensively employed in neural repair applications [204,230]. In addition, conductive biomaterials can promote neural-network formation and axonal extension by reconstructing local electrophysiological microenvironments [231,232]. However, whether these regenerative effects are mediated directly through specific immune-cell subsets still requires further quantitative investigation. When combined with exogenous electrical stimulation or photoelectric conversion strategies, such biomaterials may simultaneously modulate neuronal activity and local inflammatory states, thereby enhancing integrated neuroregenerative outcomes, although direct in vivo evidence linking immune-cell-specific mechanisms to the observed neuroregenerative outcomes remains limited [233,234]. Recent advances indicate that neural repair biomaterials are transitioning from passive soft scaffolds to multifunctional platforms that integrate mechanical matching, structural guidance, immunomodulation, fibrotic-scar remodeling, and spatiotemporal therapeutic delivery. Mechanically optimized hydrogels regulate fibrotic-scar remodeling and facilitate axon regeneration [235,236], whereas multifunctional conduits orchestrate inflammation control and neural repair through spatiotemporal delivery of bioactive factors [237].

5.2. Drug delivery

In the field of drug delivery, the central innovation of mechano-immunomodulatory biomaterials lies in the utilization of endogenous mechanical signals, including blood-flow shear stress, tissue pressure, and cellular mechanical forces, as triggering cues to achieve drug release within defined spatiotemporal windows [[238], [239], [240]] (Fig. 7). Compared with conventional delivery systems that primarily rely on chemical stimuli, these platforms are more compatible with the biomechanical characteristics of pathological microenvironments, thereby improving localized therapeutic efficacy. For example, the platelet-microcapsule hybrid system developed exploits platelet contraction forces following activation to trigger the release of encapsulated hemostatic factors [241]. These studies establish proof-of-concept for mechanically triggered drug release as a clinically viable strategy, although its clinical relevance and immunological benefit remain dependent on disease context, therapeutic cargo, release kinetics, safety, and further preclinical or clinical validation. Therefore, the immunological benefits of these systems across different disease contexts still require validation based on the specific therapeutic cargoes and biological targets involved [242].

Fig. 7.

Application of mechano-immunomodulatory biomaterials in drug delivery system.

Beyond simple “on-off” release mechanisms, the mechanical properties of biomaterials themselves can also shape interactions between delivery carriers and immune cells, thereby influencing delivery fate and therapeutic outcomes [243,244]. For instance, particle stiffness, morphology, and surface ligand presentation may alter macrophage recognition, phagocytosis, and intracellular trafficking pathways. Building upon this concept, recent core-shell microsphere systems have begun integrating “stage-specific release” with “immune-phase transitions.” Typically, the outer layer rapidly releases early anti-inflammatory or antioxidant agents, whereas the inner layer provides sustained delivery of subsequent pro-regenerative factors, with the aim of facilitating tissue progression from inflammatory to regenerative phases [245,246]. Nevertheless, whether specific biomaterial systems can truly achieve the complete sequence of “programmed neutrophil clearance-macrophage phenotypic transition-regeneration promotion” still requires rigorous validation across diverse disease models.

5.3. Integration of diagnosis and treatment

Complex diseases, particularly solid tumors and fibrotic disorders, are frequently accompanied by pronounced pathological mechanical remodeling, including matrix stiffening, solid stress accumulation, and elevated IFP. These aberrant mechanical states are often closely associated with immunosuppressive microenvironments [247,248]. By actively remodeling pathological tissue mechanics, mechano-immunomodulatory biomaterials can alleviate immunosuppression and enhance therapeutic efficacy while simultaneously integrating diagnostic and monitoring functionalities to establish theranostic mechano-immunotherapeutic platforms [249] (Fig. 8).

Fig. 8.

Application of mechano-immunomodulatory biomaterials in cancer theranostics and immune monitoring.

In cancer immunotherapy, matrix stiffening and elevated IFP within the tumor microenvironment are recognized as major physical barriers that limit immune-cell infiltration and drug delivery [247,250]. Although the mechanical stiffness of most solid tumors is generally greater than that of corresponding normal tissues, the absolute stiffness range varies substantially depending on tumor type, measurement scale, and characterization methodology. Therefore, it should not be oversimplified as a universal range of “tens to hundreds of kilopascals” [248,251]. To overcome these physical barriers, a variety of strategies have recently emerged, including matrix-remodeling approaches, enzyme-responsive softening hydrogels, and stress-/pressure-relieving nanoplatforms. Despite their distinct mechanisms, these strategies share the common objective of alleviating dense ECM accumulation, reducing local stress and interstitial pressure, and improving immune-cell infiltration together with intratumoral drug transport [249,252]. For example, nanoplatforms designed to reduce tumor interstitial pressure have been employed to enhance intratumoral drug distribution and synergistic therapeutic efficacy [188]. Nevertheless, the proposition that “precisely softening local stiffness to a defined kilopascal window can stably drive macrophage polarization toward the M1 phenotype and synergize with immune checkpoint blockade” still lacks sufficiently broad and consistent direct evidence and therefore should be interpreted cautiously.

A comprehensive understanding of the tumor mechanical immune microenvironment requires consideration of cancer-associated fibroblasts (CAFs) and ECM remodeling. As key stromal organizers, CAFs deposit and remodel collagen, fibronectin, and other ECM components while generating actomyosin-dependent contractile forces [253]. These processes increase matrix stiffness, collagen alignment, solid stress, and interstitial transport barriers, creating mechanically restrictive and immunosuppressive niches [253,254]. LOX and LOX-like enzymes further catalyze collagen crosslinking and ECM stiffening, thereby limiting CD8⁺ T-cell infiltration and promoting immune exclusion [255]. CAF- and collagen-rich stromal regions can sequester effector T cells away from tumor nests and are associated with reduced responsiveness to immune checkpoint blockade [256,257]. In parallel, stiff and crosslinked ECM promotes macrophage reprogramming toward immunosuppressive tumor-associated phenotypes by modulating integrin engagement, cytoskeletal tension, YAP/TAZ activity, and mechanosensitive ion-channel signaling [15,21,253,254]. Thus, CAF-driven ECM remodeling should be viewed not merely as a structural barrier to drug delivery but as an active mechanical regulator of antitumor immunity.

With the rapid development of multifunctional biomaterials, including conductive and piezoelectric systems, mechano-immunomodulatory platforms have begun to acquire preliminary monitoring and feedback capabilities, thereby laying the foundation for integrated theranostic systems. For example, ultrasound elastography and magnetic resonance elastography can quantitatively assess tissue stiffness, indirectly reflecting ECM remodeling, fibrosis severity, and tumor mechanical states while simultaneously providing noninvasive readouts for studies investigating mechanics-immunity interactions [258]. Similarly, piezoelectric scaffolds for bone and soft-tissue repair can convert mechanical strain into electrical signals, thereby providing localized stimulation and potentially coupling with external readout modules to monitor mechanical changes and tissue-repair progression within implanted regions [187,259]. Likewise, conductive and photoresponsive scaffolds can simultaneously regulate neuronal activity and local immune microenvironments under external electrical or optical stimulation. However, their real-time monitoring capabilities currently remain largely at the proof-of-concept or early-platform stage [234]. Looking forward, advances in implantable sensors, wireless communication technologies, and intelligent control algorithms may enable the development of integrated mechano-immunotherapeutic platforms that combine “mechanical intervention-immune activation-real-time monitoring,” thereby advancing precision theranostics for complex diseases such as cancer, fibrosis, and chronic inflammatory disorders.

To illustrate the translational potential of mechanically immunomodulatory biomaterials, Table 4 summarizes representative applications based on mechanical design parameters, immune cell targets, disease models, and translational stages.

Table 4.

Translational application summary: Disease models, material platforms, immune targets, and evidence stage.

Application Area	Representative Material Platform	Key Mechanical Design Parameter	Target Immune Cell/Outcome	Disease Model/Context	Evidence Stage	Representative References
Bone Regeneration	Piezoelectric scaffolds (3D printed, shape-memory)	Mechanoelectric coupling (piezoelectric charge generation under strain)	Macrophage pro-regenerative polarization + osteogenic stimulation	Bone defect (rat/rabbit calvarial or femoral models)	Preclinical (in vivo, small animal)	[187,215]
	Honeycomb TiO2 nanostructured implants	Surface topography (∼90 nm pore size)	Macrophage phenotypic regulation to enhanced osseointegration	Implant-bone interface (rat femoral model)	Preclinical (in vivo, small animal)	[17]
	Gradient-stiffness hydrogel scaffolds (Mn2+/Mg-doped HAP@Fe3O4)	Continuous mechanical gradient + ion release	BMSC chondrogenic/osteogenic differentiation; immune microenvironment modulation	Osteochondral defect (rabbit model)	Preclinical (in vivo, small animal)	[211]
	Hydrogel (80 kPa stiffness)	Defined substrate stiffness targeting Piezo1 inhibition	Attenuated inflammation in skin and bone tissues via Piezo1-mediated mechanotransduction inhibition	Skin and bone tissue (mouse model)	Preclinical (in vivo, small animal)	[36]
Skin/Wound Healing	Stimuli-responsive hydrogels (temperature, pH, ROS, glucose)	Dynamic network architecture; stiffness modulation in response to environmental changes	Sequential immune phase transitions (neutrophil clearance to macrophage phenotypic shift to regeneration)	Chronic wound, diabetic wound (mouse/rat models)	Preclinical (in vivo, small animal); design hypothesis stage for sequential mechano-immune programming	[219,220]
	Hydrogel-aerogel biphase gel (HAB-gel)	Self-negative pressure + exudate absorption	Pro-regenerative macrophage polarization + antibacterial	Chronic wound (rat model)	Preclinical (in vivo, small animal)	[189]
Tendon/Tendon-Bone Interface	Biomimetic aligned fiber-bundle scaffolds	Aligned surface topography + tensile mechanical properties matching native tendon	Ordered collagen reconstruction via immune-matrix interaction	Rotator cuff/tendon injury (large animal models)	Preclinical (in vivo, small and large animal)	[216,221]
Vascular Regeneration	Compliance-matched small-diameter vascular grafts; hierarchically aligned fibrous scaffolds	Compliance matching + fiber alignment + fluid shear stress	Macrophage phenotypic regulation + endothelial cell recruitment to graft patency	Small-diameter vascular graft (rat/rabbit model)	Preclinical (in vivo, small animal)	[224,225]
Neural Regeneration	Ultra-soft hyaluronic acid-based hydrogels; conductive biomaterials (PEDOT:PSS)	Ultra-low stiffness (0.1–1 kPa) matching neural tissue + conductivity for electrophysiological support	Microglia/astrocyte modulation to minimize glial scar; neural network formation	Spinal cord injury (rat model)	Preclinical (in vivo, small animal); proof-of-concept for combined mechano-electrical immune modulation	[204,231,234]
Mechano-Responsive Drug Delivery	Platelet-microcapsule hybrid system	Platelet contraction force as mechanical trigger for drug release	Targeted hemostatic factor release at site of platelet activation	Hemostasis/thrombosis (in vitro proof-of-concept + preclinical)	Preclinical (in vitro to small animal)	[241]
	Core-shell microsphere systems	Stage-specific degradation for sequential release	Outer layer: early anti-inflammatory agents; Inner layer: sustained pro-regenerative factors	Wound healing, rheumatoid arthritis (mouse models)	Preclinical (in vivo, small animal)	[245,246]
	DNA mechanocapsules	Programmable piconewton-responsive mechanical trigger	Spatiotemporally gated release in response to cell-generated forces	In vitro proof-of-concept	Early-stage (in vitro)	[240]
Cancer Theranostics	Tumor IFP-reducing nanoplatforms; enzyme-responsive softening hydrogels	Tumor ECM remodeling: stiffness reduction, IFP normalization	Enhanced immune cell infiltration + intratumoral drug delivery; potential synergy with immune checkpoint blockade	Solid tumor (mouse tumor models)	Preclinical (in vivo, small animal); "precise stiffness window for M1 polarization + ICB synergy" remains a design hypothesis	[188,249]
	Ultrasound/MR elastography + piezoelectric scaffolds	Real-time mechanical monitoring + localized electrical stimulation	Integrated "mechanical intervention to immune activation to real-time monitoring"	Bone defect, soft tissue repair (proof-of-concept)	Early-stage platform; real-time closed-loop monitoring remains largely at proof-of-concept	[187,258]
Immune Cell Engineering	High-stiffness cellular backpacks (∼50 MPa)	Mechanical stiffness of membrane-anchored particles	Activation of innate immune response in DCs and macrophages via stiffness-enhanced inflammatory programs	In vitro/ex vivo immune cell engineering	Early-stage (in vitro)	[179]

6. Challenges and future perspectives

6.1. Current challenges

6.1.1. Multidimensional complexity of mechanical signals and heterogeneity of immune responses

Progress in mechano-immunomodulatory biomaterials has been substantial, yet several structural challenges constrain translational advancement. Tissue microenvironments present mechanical signals of intrinsic multidimensionality: stiffness, viscoelasticity, fluid shear stress, compressive load, and interstitial pressure coexist in vivo and act upon immune cells in a highly spatiotemporally heterogeneous manner, making it difficult to isolate the independent contribution of any single mechanical variable to immune regulation.

A second structural challenge lies in cellular heterogeneity. Macrophages, dendritic cells, neutrophils, and T cells each possess distinct mechanosensory repertoires; in response to nominally identical mechanical cues, these populations can exhibit divergent or opposing outcomes across migration mode, activation state, phagocytic capacity, and cytokine profile. Phenotypic heterogeneity within each subset compounds this further, rendering universally applicable mechanistic rules elusive and motivating cell-type-resolved experimental designs.

6.1.2. Limitations of physiological mechanical models and experimental standardization

Although in vitro mechanobiological models have improved considerably, the prevailing 2D culture systems and static 3D culture platforms cannot recapitulate the cyclic mechanical loading, interstitial flow, and spatiotemporal stiffness gradients that characterize living tissues.

Furthermore, methodologies for measuring and reporting mechanical parameters remain insufficiently standardized, making it difficult to directly compare and systematically integrate results across different studies. Even within identical experimental systems, microscale structural heterogeneity introduced during biomaterial fabrication can alter local stress distributions and further compromise experimental reproducibility. Consequently, the development of multimodal experimental platforms capable of reproducing physiologically relevant mechanical environments, together with standardized metrics and reporting guidelines for biomechanical characterization, will be essential for improving the reliability, reproducibility, and comparability of mechano-immunomodulatory research.

6.1.3. Translational barriers of mechano-immunomodulatory biomaterials

Translating fundamental discoveries in mechano-immunology into the design of mechano-immunomodulatory biomaterials presents substantial technical and regulatory challenges on the path from conceptual innovation to clinical implementation. Mechanical properties are often highly sensitive to fabrication conditions, making batch-to-batch consistency difficult to maintain and thereby complicating product quality control. In practical clinical translation, additional considerations include biomechanical variability across different disease models, distinct physical loading environments, and interpatient differences in tissue mechanics. These complexities necessitate the development of preclinical animal models and translational evaluation frameworks that more accurately recapitulate clinical scenarios. Consequently, the successful clinical implementation of mechano-immunomodulatory biomaterials will require interdisciplinary standardized testing platforms together with scalable translational strategies addressing manufacturability, biosafety, and regulatory acceptance. In addition, translational barriers differ across material classes. Each platform faces distinct challenges in manufacturing, sterilization, quality control, and regulation. Hydrogels, implant coatings, piezoelectric scaffolds, and nanodelivery systems therefore need material-specific translational frameworks. Hydrogels require precise control of crosslinking, swelling, degradation, sterility, and release profiles. Implant coatings require careful evaluation of coating adhesion, wear resistance, interfacial stability, and manufacturing reproducibility. Piezoelectric scaffolds require additional assessment of electromechanical output, polarization stability, fatigue behavior, and degradation-related safety. Nanodelivery systems require strict control of particle size distribution, surface properties, loading efficiency, release kinetics, biodistribution, and immunotoxicity. Regulatory pathways also vary. They depend on the intended use, primary mode of action, and whether the system includes device, drug, or biologic components. Therefore, material-specific translational matrices are needed. These matrices can guide early-stage design, preclinical evaluation, and regulatory planning.

6.1.4. Challenges in integrating interdisciplinary methodological frameworks

Mechano-immunology is inherently an interdisciplinary field situated at the intersection of mechanobiology, immunology, and materials science. However, substantial differences remain among these disciplines with respect to theoretical frameworks, terminology definitions, and validation standards. For example, materials science primarily emphasizes the controllability of mechanical properties and engineering parameters, whereas immunology focuses more strongly on cellular signaling pathways and inflammatory outcomes. As a result, the investigative scales and evaluation metrics adopted by these disciplines are often not fully compatible.

Such paradigm differences create significant interdisciplinary communication barriers during the formulation of research questions, the design of experimental strategies, and the interpretation of experimental findings, and may even lead to conceptual misunderstandings or model-related biases. Therefore, promoting collaborative efforts to establish standardized terminology, experimental guidelines, and data-sharing frameworks will be essential for achieving coordinated progress and successful translational advancement in mechano-immunology research.

6.2. Future directions and emerging trends

6.2.1. Multimodal data-driven design of mechano-immunomodulatory biomaterials

The future development of mechano-immunomodulatory biomaterials is expected to progressively evolve from traditional empirical screening toward multimodal data-driven system optimization (Fig. 9). Rather than evaluating biomaterials solely on the basis of individual mechanical parameters or endpoint biological readouts, next-generation design frameworks should integrate diverse material dimensions, including composition, stiffness, viscoelasticity, stress-relaxation behavior, surface topography, pore architecture, conductive/piezoelectric characteristics, degradation profiles, and drug-release kinetics. These material parameters should be further coupled with multilayered biological datasets encompassing single-cell omics, spatial transcriptomics, high-content imaging, continuous monitoring signals, immune-cell lineage trajectories, cytokine networks, and tissue-regeneration outcomes. Particularly in mechano-immunomodulatory systems, material parameters do not function as isolated variables. Instead, they dynamically interact with cell-matrix interactions, mechanosensing pathways, and microenvironmental remodeling processes to form an integrated regulatory network. Consequently, future efforts urgently require the establishment of standardized “materials-mechanics-immunity-regeneration” databases together with unified data standards. The accumulation of high-quality, longitudinal, and structured datasets will provide an essential foundation for artificial intelligence (AI)-driven models to identify critical regulatory windows, uncover hidden mechanistic relationships, and achieve robust cross-laboratory generalization.

Fig. 9.

Future directions of AI-enabled mechano-immunomodulatory biomaterials.

Recent advances in AI-driven materials design have enabled the integration of molecular descriptors, compositional features, processing parameters, and experimental readouts to predict degradation behavior, mechanical properties, biocompatibility, and functional performance. Extending these approaches to mechano-immunomodulatory biomaterials could uncover non-intuitive combinations of stiffness, viscoelasticity, porosity, surface topography, degradation kinetics, ion release, and immunomodulatory payloads that are difficult to identify using conventional one-factor-at-a-time optimization.

6.2.2. Hybrid modeling integrating AI and biophysical coupling

Exclusive reliance on black-box machine learning approaches for fitting and predicting biomaterial performance is unlikely to satisfy the demands of mechanistic interpretation and translational application in the field of mechano-immunomodulatory biomaterials. In contrast, the development of hybrid models integrating AI with biophysical mechanisms holds substantial promise. AI-guided mechano-immunomodulatory biomaterial design begins with standardized materials–mechanics–immunity datasets. These datasets integrate material chemistry, processing conditions, mechanical properties, degradation profiles, immune-cell phenotypes, cytokine networks, single-cell omics, imaging features, and in vivo therapeutic outcomes. These datasets enable multimodal feature representations and physics-informed or mechanism-guided models that integrate finite-element analysis, reaction–diffusion transport, cell–matrix interactions, and agent-based immune-cell simulations. The resulting models can then identify candidate biomaterial designs using interpretable machine learning, Bayesian optimization, generative models, and reinforcement learning, followed by experimental validation through high-throughput mechanical characterization, immune-cell assays, microfluidic systems, organ-on-a-chip platforms, and disease-relevant animal models. Experimental data are subsequently fed back into the design framework through active learning, enabling iterative refinement of mechanical design windows and ultimately supporting patient- and disease-stage-specific mechano-immunomodulatory biomaterials.

6.2.3. Emergence of digital twin systems for pathological microenvironments

Inspired by the concepts of virtual cells and virtual organoids, future mechano-immunology research may conceptualize the diverse cellular populations involved in immune mechanoregulation as parameterizable and continuously updatable virtual functional units, whose responses to mechanical cues, metabolic states, and pharmacological stimulation can be digitally represented. Simultaneously, material mechanical properties, degradation behaviors, and release characteristics can be incorporated into a unified computational framework, thereby enabling the reconstruction of the dynamic evolution of injury- and disease-associated microenvironments within virtual environments. Such design frameworks would allow researchers to predict the long-term effects of distinct structural parameters on immune microenvironment remodeling and regenerative trajectories in silico, thereby promoting a transition from “passive material screening” toward the rational engineering of therapeutic systems. In complex clinical scenarios, including chronic wounds, bone defects, tendon-interface repair, and postoperative local immune modulation following tumor resection, digital twin platforms may ultimately function as critical bridges connecting in vitro experimentation, mechanistic investigation, and clinical intervention.

6.2.4. Personalized medicine as a major future direction

Substantial interpatient variability exists in baseline inflammatory states, immunosenescence, local tissue mechanical properties, defect morphology, vascular supply, and clinical history, all of which can directly influence host responses and regenerative outcomes following biomaterial implantation. By integrating multimodal digital models with digital twin systems, future strategies may incorporate patient-derived omics datasets, tissue imaging, dynamic biomarkers, clinical phenotypes, and in vitro model readouts. Such integrated datasets could enable the design of patient-specific stiffness profiles, surface topographies, pore architectures, drug-loading configurations, and stimulation modalities. These personalized approaches could be applied to complex pathological scenarios including diabetic chronic wounds, bone defects, tendon-bone interface injuries, and local immune remodeling following tumor resection. Precision biomaterials engineering based on these strategies holds considerable promise for improving therapeutic efficacy while simultaneously reducing the risks of aberrant inflammation, fibrosis, and regenerative failure. Ultimately, these advances may drive the transition of mechano-immunomodulatory biomaterials from generalized platforms toward truly precision therapeutic systems.

7. Conclusion

Mechano-immunomodulation, as an emerging interdisciplinary field at the intersection of mechanobiology, immunology, and biomaterials science, is fundamentally reshaping the design principles and developmental paradigms of immunomodulatory biomaterials. This review systematically summarizes the biological foundations, molecular mechanisms, and biomaterials engineering strategies through which mechanical signals regulate host immune responses, while further highlighting the translational potential of mechano-immunomodulatory platforms in tissue regeneration, drug delivery, and theranostic applications. Meanwhile, the emergence of AI-integrated biophysical modeling and digital twin systems for pathological microenvironments is expected to enable the prediction and optimization of dynamic material-immune-regeneration coupling processes within computational environments, thereby accelerating the translational trajectory from fundamental discoveries to clinical intervention. Ultimately, personalized mechano-immunomodulatory biomaterials tailored to complex clinical scenarios are poised to become foundational enabling technologies for the advancement of precision medicine. We are currently at a pivotal stage in the transition of mechano-immunomodulatory biomaterials from proof-of-concept validation toward clinical translation. Deep interdisciplinary integration, together with the establishment of standardized frameworks, will serve as key driving forces propelling the continued advancement of this field.

Ethics approval and consent to participate

Confirm that no ethical issues are involved.

CRediT authorship contribution statement

Ruiyue Hang: Conceptualization, Writing – original draft. Xiaohong Yao: Funding acquisition, Project administration, Resources, Supervision. Long Bai: Conceptualization, Funding acquisition, Supervision, Writing – review & editing. Yin Xiao: Conceptualization, Writing – review & editing. Ruiqiang Hang: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.

Declaration of competing interest

Long Bai is an editorial board member for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests. All authors declare no conflict of interest.

Abbreviations list

ECM

extracellular matrix

IFP

interstitial fluid pressure

YAP

Yes-associated protein

TAZ

transcriptional coactivator with PDZ-binding motif

CD8

cluster of differentiation 8

ROS

reactive oxygen species

NETs

neutrophil extracellular traps

DNA

deoxyribonucleic acid

TNF-α

tumor necrosis factor-α;

IL-1β

interleukin-1β

IL-6

interleukin-6

IL-10

interleukin-10

TGF-β

transforming growth factor-β;

Th1

T helper 1

Th2

T helper 2

Th17

T helper 17

Treg

regulatory T cell

PEG

polyethylene glycol

NF-κB

nuclear factor-κB

GTP

guanosine triphosphate

Rac1

Ras-related C3 botulinum toxin substrate 1

RhoA

Ras homolog family member A

TCR

T-cell receptor

BCR

B-cell receptor

CD69

cluster of differentiation 69

PKCβ

protein kinase C β

FAK

focal adhesion kinase

ICAM-1

intercellular adhesion molecule 1

VCAM-1

vascular cell adhesion molecule 1

IL-4

interleukin-4

CSF1

colony-stimulating factor 1

LPS

lipopolysaccharide;

IFN-γ

interferon-γ;

αMβ2

integrin alpha M beta 2

Mac-1

macrophage-1 antigen

CD11b/CD18

cluster of differentiation 11b/18

TRPV4

transient receptor potential vanilloid 4

ROCK

Rho-associated coiled-coil-containing protein kinase

CD83

cluster of differentiation 83

CD86

cluster of differentiation 86

MHC-II

major histocompatibility complex class II

IL-12

interleukin-12

TGF-β1

transforming growth factor-β1

CCR7

C-C chemokine receptor type 7

SIRT1

sirtuin 1

HIF-1α

hypoxia-inducible factor 1α

DC

dendritic cell

LFA-1

lymphocyte function-associated antigen-1

αLβ2

integrin alpha L beta 2

APC

antigen-presenting cell

CTL

cytotoxic T lymphocyte

VLA-4

very late antigen-4

α4β1

integrin alpha 4 beta 1

Nox4

NADPH oxidase 4

Aβ

amyloid-β;

AFM

atomic force microscopy

Src

proto-oncogene tyrosine-protein kinase Src

TRPV

transient receptor potential vanilloid

TRPM

transient receptor potential melastatin

TLR4

Toll-like receptor 4

CaMKII

Ca²⁺/calmodulin-dependent protein kinase II

MST1/2

mammalian sterile 20-like kinase 1/2

IRF-1

interferon regulatory factor 1

IL-15

interleukin-15

TRPM7

transient receptor potential melastatin 7

IRF3

interferon regulatory factor 3

Cdc42

cell division control protein 42 homolog

GEF

guanine nucleotide exchange factor

GAP

GTPase-activating protein

LATS1/2

large tumor suppressor kinase 1/2

MAPK

mitogen-activated protein kinase

GSK-3β

glycogen synthase kinase-3β

STAT3

signal transducer and activator of transcription 3

LINC

linker of nucleoskeleton and cytoskeleton

SUN

Sad1 and UNC-84 domain-containing protein

KASH

Klarsicht/ANC-1/Syne homology

SUN1/2

SUN-domain protein 1/2

TLR

Toll-like receptor

TEAD

TEA domain transcription factor

IκB

inhibitor of κB

ERK

extracellular signal-regulated kinase

JNK

c-Jun N-terminal kinase

p38

p38 mitogen-activated protein kinase

pMHC

peptide-major histocompatibility complex

CD25

cluster of differentiation 25

IL-2

interleukin-2

OXPHOS

oxidative phosphorylation

GLUT1

glucose transporter 1

Lars2

mitochondrial leucyl-tRNA synthetase 2

Drp1

dynamin-related protein 1

THP-1

human monocytic leukemia cell line;

SK

shish-kebab

PCL

polycaprolactone

TRP

transient receptor potential

HAB

hydrogel-aerogel biphase

HAP

hydroxyapatite;

CD80/CD86

cluster of differentiation 80/86

BMSC

bone marrow mesenchymal stem cell

CAF

cancer-associated fibroblast

LOX

lysyl oxidase

PEDOT:PSS

poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)

ICB

immune checkpoint blockade

MR

magnetic resonance

Appendix ASupplementary data

The following is the Supplementary data to this article: