Proteoglycan‐Mimetic Bottle‐Brush Polymer Brushes for Osteoarthritis Therapy: Lubrication Enhancement and Multifunctional Disease Modulation

ABSTRACT

Lubrication is essential for maintaining joint health and enabling smooth articulation. In healthy joints, natural lubricants such as proteoglycans endow articular cartilage with an exceptionally low coefficient of friction. Notably, proteoglycans possess a characteristic bottle‐brush architecture that generates robust hydration layers at the cartilage surface, thereby facilitating effective lubrication. In osteoarthritis (OA), degradation of extracellular matrix components, depletion of proteoglycans, and increased friction and wear at inflamed joint interfaces collectively accelerate disease progression. Therefore, restoring joint lubrication has emerged as a promising strategy to reduce friction‐induced damage and delay OA progression. In recent years, extensive efforts have been devoted to developing biomimetic lubricants, particularly proteoglycan‐mimetic polymer brushes inspired by natural proteoglycan architectures. These systems are designed to replicate the bottle‐brush architecture and hydration lubrication mechanism of native proteoglycans. In this review, we summarize the fundamental lubrication mechanisms of articular cartilage, with emphasis on boundary and hydration lubrication mediated by proteoglycans, and discuss the design principles and representative material systems of proteoglycan‐mimetic polymer brushes. By linking native lubrication mechanisms with biomimetic brush design and translational considerations, this review highlights proteoglycan‐inspired polymer brushes as promising disease‐modifying candidates for OA treatment.

This review emphasizes the strategies and applications of proteoglycan‐mimetic bottle‐brush polymers for osteoarthritis (OA) treatment. Four categories are discussed: HA‐based brushes, PC‐based lubricants, dual‐polymer synergistic systems, and other types of polymer brushes. These biomimetic platforms achieve integrated functions including enhanced lubrication, anti‐inflammatory drug delivery, and cartilage protection, thereby providing a disease‐modifying therapy for OA.

1. Introduction

Osteoarthritis (OA) is a prevalent joint disorder characterized by pain, swelling, stiffness, functional impairment, and even disability. Once established, OA is largely irreversible, resulting in substantial physical and psychological burdens and imposing considerable socioeconomic costs [1, 2, 3, 4]. Pathologically, OA is marked by progressive thinning and degeneration of articular cartilage, synovial inflammation, osteophyte formation, and subchondral bone remodeling [5, 6, 7]. Due to the avascular and dense nature of cartilage, its intrinsic self‐repair capacity is extremely limited [8]. The development and progression of OA are driven by multiple factors, including aging, obesity, trauma, mechanical overloading, and metabolic and inflammatory abnormalities [4, 9, 10, 11, 12]. Among these, degradation of articular cartilage is a central event in disease initiation and progression. Mechanical or biochemical insults disrupt cartilage matrix integrity and impair boundary lubrication, leading to increased friction and wear between opposing cartilage surfaces [13, 14]. These changes further induce chondrocyte death through apoptosis, necroptosis, pyroptosis, and necrosis, ultimately disturbing cartilage homeostasis [15]. Moreover, cartilage fragments and matrix degradation products act as damage‐associated molecular patterns (DAMPs), which activate synoviocytes and immune cells, sustain inflammation, and drive catabolic cascades that culminate in joint destruction and aberrant bone remodeling [7, 16, 17, 18]. Pro‐inflammatory cytokines, matrix metalloproteinases, alarmins (e.g., S100A8 and S100A9), complement components, and oxidative stress further amplify OA progression via MAPK and NF‐κB signaling pathways [19, 20, 21, 22, 23].

Current OA management relies on pharmacological and non‐pharmacological strategies. Pharmacological therapies, including analgesics, nonsteroidal anti‐inflammatory drugs, and intra‐articular corticosteroids, mainly provide symptomatic relief but are associated with significant adverse effects upon long‐term use, such as gastrointestinal and renal complications. Non‐pharmacological approaches, primarily joint replacement surgery, can restore function in end‐stage disease but are invasive and costly [24]. These limitations highlight the urgent need for disease‐modifying and structure‐preserving therapeutic strategies, especially at early OA stages.

Within the joint cavity, synovial fluid and the articular cartilage surface together form one of the most efficient natural lubrication systems [25]. Articular cartilage sustains substantial mechanical loads while maintaining an exceptionally low friction coefficient under physiologic conditions [26, 27]. This remarkable performance is largely attributed to synovial fluid, a complex biological lubricant composed of hyaluronic acid (HA), proteoglycans, proteoglycan 4 (lubricin), chondroitin sulfate, phospholipids, and other biomacromolecules [26, 28, 29, 30]. These components synergistically reduce friction, protect cartilage surfaces, and mitigate wear‐induced degeneration. Among these, proteoglycans (Figure 1) account for approximately 5%–10% of synovial fluid and play a pivotal role in cartilage mechanics and lubrication [31]. Their characteristic bottle‐brush architecture, consisting of a core protein and covalently attached glycosaminoglycan (GAG) chains (e.g., chondroitin sulfate and keratan sulfate) generates a highly charged and hydrated environment that supports both load‐bearing and lubrication. The negatively charged sulfate groups attract abundant water molecules, forming a stable hydration layer on the cartilage surface and enabling effective hydration lubrication [32, 33, 34, 35, 36, 37, 38]. Lubricin (proteoglycan 4) (Figure 2), a glycoprotein enriched in the superficial zone of cartilage, also exhibits a bottle‐brush‐like structure with a negatively charged mucin‐like domain and non‐glycosylated terminal domains [39, 40]. It plays a pivotal role in boundary lubrication and chondroprotection by reducing cell adhesion, inhibiting synoviocyte overproliferation, and preventing chondrocyte apoptosis and hypertrophy [41, 42, 43, 44]. In addition, HA contributes to lubrication through its viscoelastic properties and CD44‐mediated signaling pathways, while phosphatidylcholine (PC) species participate in both boundary and hydration lubrication at the cartilage interface [45, 46, 47, 48, 49, 50].

FIGURE 1.

Schematic structure of a proteoglycan monomer molecule. Proteoglycans are formed by covalent binding of core proteins and glycosaminoglycans (Chondroitin Sulfate and Keratin Sulfate). The core protein contains three globular domains (G1, G2, and G3), and there are also some O‐linked oligosaccharides and N‐linked oligosaccharides attached to the core protein. The negative charge on the GAG chain attracts water molecules, causing the proteoglycan to form a hydrated layer.

FIGURE 2.

Schematic structure of lubricin. Lubricin has a negatively charged mucin‐like domain in its center and positively charged N‐ and O‐terminal domains at both ends (SMB and PEX).

Collectively, these bottle‐brush‐like biomolecules and their supramolecular assemblies endow cartilage with exceptional hydration capacity, enabling ultralow friction even under high loads. Several lubricating biological fluids in the human body contain functional biomolecules that facilitate movement and reduce friction; their composition, friction coefficients, and associated diseases are summarized in Table 1. Inspired by these natural lubrication systems, increasing efforts have been devoted to developing biomimetic lubricants for OA therapy. Recently, multifunctional nanomaterials integrating lubrication enhancement and drug delivery have emerged as promising strategies [51]. Representative examples include mesoporous silica nanoparticle‐based platforms, in which phospholipid or hydration‐lubricating polymer coatings provide boundary/hydration lubrication while mesoporous structures enable local drug loading and release [52], as well as self‐assembled organic polymer nanoparticles that combine interfacial lubrication with anti‐inflammatory or chondroprotective drug delivery [53]. This review focuses specifically on proteoglycan‐mimetic bottle‐brush polymer brushes, which directly emulate the architecture and hydration lubrication mechanism of native proteoglycans. We highlight their design principles, representative material systems, and current challenges toward clinical translation. Figure 3 provides a schematic overview of representative proteoglycan‐mimetic polymer brush systems for joint lubrication and OA therapy.

TABLE 1.

Summary of friction coefficients, native lubricants, and related diseases of motor system tissues.

Biological tissue	Tissue/tissue interface	COF	Native lubricant	Contributing molecules	Associated diseases/injury
Joint	Cartilage‐cartilage	0.001–0.100 [28]	Synovial fluid	HA, CS, LUB, lipids	Osteoarthritis
Tendon	Tendon‐surrounding tissue	0.005–0.014 [62]	Sheath fluid	HA, LUB, lipids	Tendinitis
Bone	Bone‐surrounding tissue	0.100–0.300 [63]	Fat	Lipids	Periostitis
Muscle	Muscle‐surrounding tissue	0.290–0.360 [64]	Fat	Lipids	Muscle strain/tear
Intervertebral disc	Nucleus pulposus‐surrounding tissue	—	Nucleus pulposus	HA, CS, aggrecan	Herniated intervertebral disc
Shoulder cuff	Shoulder‐surrounding tissue	0.002 [65]	Synovial fluid	HA, LUB, lipids	Rotator cuff injury/tear
Ligament	Ligament‐surrounding tissue	—	—	—	Ligament sprain/tear

FIGURE 3.

Schematic overview of representative proteoglycan‐mimetic polymer brush systems for joint lubrication and osteoarthritis therapy. These systems include phosphatidylcholine (PC)‐based polymer brushes, hyaluronic acid (HA)‐based polymer brushes, other functional polymer brushes, and dual‐polymer synergistic brushes. Adapted with permission from Yan R et al. [54], Copyright 2023 American Chemical Society; Moon H H et al. [55], Copyright The Royal Society of Chemistry 2022; Chen H et al. [56], Copyright 2020 Elsevier Ltd; Xiong D et al. [57], Copyright The Authors 2025; Xie R J et al. [58], Copyright 2021, The Author(s), under exclusive licence to Springer Nature Limited; Liu G et al. [59], Copyright 2014 American Chemical Society; Zhang M et al. [60], Copyright The Royal Society of Chemistry 2023; Kahle E R et al. [61], Copyright 2024 The Authors. Published by American Chemical Society. Licensed under CC‐BY 4.0.

2. Native Lubrication Mechanisms and Biomimetic Implications

Proteoglycans (Figure 4) are bottle‐brush‐like biomolecules characterized by a distinctive architecture consisting of a polypeptide backbone and densely grafted polysaccharide side chains. They typically possess hydrophobic moieties at one or both termini and hydrophilic sugar groups distributed along the central segment. When proteoglycans interact with hyaluronic acid (HA), their hydrophobic termini adsorb onto the long HA chain, increasing the interfacial contact area and stabilizing the association via hydrophobic effects. Meanwhile, the hydrophilic glycosaminoglycan (GAG) chains extend outward into the aqueous environment, where they strongly interact with surrounding water molecules to form a highly hydrated layer. As a result, proteoglycans assemble with HA into hierarchical bottle‐brush‐like supramolecular complexes, in which HA serves as the main chain and proteoglycans function as side chains. This hierarchical architecture substantially increases the effective surface area and hydration capacity, thereby optimizing joint lubrication and mitigating friction‐induced wear during articulation.

FIGURE 4.

Schematic diagram of the bottle‐brush‐like structure of proteoglycans. Proteoglycans are connected to hyaluronic acid through their hydrophobic ends and interact with water molecules through their hydrophilic sugar groups.

The primary lubricating mechanisms in articular joints include fluid film lubrication, boundary lubrication, and hydration lubrication. Fluid film lubrication predominates under low loads and high‐sliding‐speed conditions, where the interstitial fluid is pressurized to form a thin load‐bearing layer that supports most of the applied stress and reduces direct mechanical contact between cartilage surfaces [66]. In contrast, boundary lubrication becomes dominant under high load, high shear, or reduced lubricant viscosity, where an adsorbed molecular layer minimizes direct solid–solid contact and surface wear [28]. For example, Seror et al. demonstrated that hyaluronic acid, phosphatidylcholine, and lubricin act synergistically‐each contributing distinct functional roles‐to achieve robust boundary lubrication at joint surfaces [67]. Hydration lubrication, first proposed by Raviv et al., represents a key mechanism underlying the ultralow friction of biological systems. It arises from the formation of strongly bound yet dynamically exchangeable hydration shells around charged or zwitterionic groups. These hydration shells can sustain high loads while maintaining rapid relaxation under shear, thereby enabling both stability and fluidity [68]. Proteoglycans contribute significantly to this mechanism by forming densely packed, hydrated layers on cartilage surfaces, which reduce friction and prevent direct surface contact [69]. In addition, the high hydrophilicity of proteoglycans supports the formation of a compact hydration layer, in which water molecules rapidly exchange with bulk water, preserving fast relaxation dynamics and ensuring low friction under shear conditions [70]. Beyond molecular‐scale interactions, proteoglycans also contribute to lubrication through structural and rheological effects. Their large, flexible polymeric chains adopt a gel‐like conformation in aqueous environments, increasing lubricant viscosity and film stability [71]. Moreover, proteoglycan aggregates can fill micro‐scale surface irregularities on cartilage, reducing effective contact area and protecting against mechanical wear [72]. Collectively, these native lubrication mechanisms provide essential design cues for artificial systems. In particular, the bottle‐brush architecture, highly hydrated charged groups, synergistic interactions among macromolecules, and stable surface anchoring collectively inspire the development of proteoglycan‐mimetic polymer brushes for OA therapy.

3. Design Principles of Proteoglycan‐Mimetic Polymer Brushes

Based on the lubrication mechanisms of native proteoglycans, several key design principles have emerged for the development of proteoglycan‐mimetic polymer brushes. These principles are primarily derived from the unique bottle‐brush architecture, hydration lubrication mechanism, and synergistic interactions observed in natural joint systems. Figure 5 shows the different lubrication mechanisms of joints and the various polymer brushes that have been developed for osteoarthritis.

FIGURE 5.

Diagram illustrating various lubrication strategies and lubricant materials for the treatment of osteoarthritis. The figure shows lubricant designs based on two mechanisms: hydration lubrication and boundary lubrication. Representative materials include: hyaluronic acid (HA)‐based lubricants (e.g., HA/PA@Lipo‐GA, HA/phosphatidylcholine polymers), HA composites (HA/HA + HA/PM, HEMA‐blended HA), and other novel lubricating materials (such as phospholipid‐coated mesoporous silica nanoparticles, thermosensitive microgels grafted with hair‐like polyelectrolyte brushes, and the ring‐shaped polymer c‐P(HEMA) core formed by SBMA and DMAEMA brushes). By mimicking the lubrication mechanisms of natural joints, these materials offer diverse strategies for supplementary lubrication therapy in osteoarthritis.

3.1. Bottle‐Brush Architecture and High Grafting Density

The molecular brush structure of proteoglycans endows articular cartilage with exceptional hydration and lubrication properties by forming dense, HA‐centered supramolecular networks. Biomimetic polymer brushes emulate this native architecture by grafting polymer side chains onto a central backbone, such as hyaluronic acid, hydrogels, or other synthetic scaffolds. Owing to the high grafting density, steric repulsion between adjacent side chains promotes chain extension and reduces entanglement, resulting in a well‐defined and highly extended brush conformation [73]. Well‐defined bottle‐brush architectures are commonly fabricated using “grafting‐from” or “grafting‐to” strategies. In particular, controlled radical polymerization methods, such as atom transfer radical polymerization (ATRP) and reversible addition–fragmentation chain‐transfer (RAFT) polymerization, enable the in situ growth of polymer side chains from initiated backbones or surfaces, allowing regulation of grafting density, side‐chain length, and brush thickness. These structural parameters directly influence chain extension, hydration layer formation, and lubrication performance [74, 75, 76, 77]. This structural feature increases the effective surface coverage and facilitates the formation of a stable interfacial layer, which is essential for maintaining lubrication under physiological loading conditions.

3.2. Hydration Lubrication Mediated by Charged and Hydrophilic Groups

A key design principle of proteoglycan‐mimetic polymer brushes is the incorporation of highly hydrated, charged, or zwitterionic groups that can strongly interact with water molecules. Similar to native proteoglycans, these hydrophilic side chains extend into the aqueous environment and form a dense hydration layer through strong water binding. Under compressive or shear loading, these hydration layers remain stable while allowing rapid molecular rearrangement, enabling low friction through hydration lubrication [78]. The dynamic exchange of water molecules within this layer ensures both load‐bearing capacity and fluidity, thereby minimizing frictional dissipation at the cartilage interface.

3.3. Cartilage Surface Interaction and Lubrication Replenishment

Another critical design consideration is the ability of polymer brushes to effectively interact with and retain on the cartilage surface. In native systems, proteoglycans bind to hyaluronic acid through linker proteins to form supramolecular aggregates, which further interact with type II collagen within the cartilage matrix, contributing to both load‐bearing and lubrication [79]. Similarly, lubricin forms complexes with HA and phospholipids, facilitating surface adsorption and reducing interfacial wear [80]. Inspired by these mechanisms, biomimetic polymer brushes are designed to adsorb onto or anchor at the cartilage surface, forming a stable lubricating layer. Upon intra‐articular injection, these materials can replenish depleted lubricants in osteoarthritic joints and restore interfacial lubrication. In addition, polymer brushes can fill micro‐scale surface irregularities, reducing effective contact area and further protecting cartilage from mechanical damage.

3.4. Functional Integration and Therapeutic Adaptability

Beyond lubrication, proteoglycan‐mimetic polymer brushes offer significant advantages in structural tunability and functional integration. Compared with conventional lubricants, these systems allow flexible polymerization strategies, controllable architectures, and facile chemical modification [81]. As a result, they can be engineered to incorporate additional functionalities, such as drug loading, anti‐inflammatory activity, and stimulus‐responsive behavior. In the context of osteoarthritis, where synovial fluid composition is altered and proteoglycans are depleted, such multifunctional systems can serve as both lubrication substitutes and therapeutic platforms. By combining lubrication enhancement with anti‐inflammatory or regenerative functions, these polymer brushes hold significant potential for slowing disease progression and improving joint function [82, 83].

4. Representative Proteoglycan‐Mimetic Polymer Brush Systems for OA

Based on the above design principles, current proteoglycan‐mimetic polymer brushes can be broadly categorized according to their dominant lubrication mechanisms and structural features. These systems primarily include phosphatidylcholine‐based, hyaluronic acid‐based, and other structurally diverse biomimetic polymer brushes. Table 2 presents the lubricating properties and mechanisms of several biomaterials developed in recent years for the treatment of osteoarthritis.

TABLE 2.

Lubrication properties and mechanisms of advanced biomaterials for articular cartilage repair.

Name	Lubrication mechanism	COF	References
Solution lubricant
Chitosan‐g‐zwitterionic copolymers	Hydration lubrication mechanism	< 0.010	[84]
Biomimetic diblock copolymer	Boundary lubrication mechanism	0.088	[85]
Bottle‐brush poly(7‐oxanorbornene‐2‐carboxylate) polyelectrolyte	Act as a viscous lubricant	0.032	[86]
Biomimetic proteoglycans	Create and maintain a boundary layer	0.009	[87]
Linear brush copolymer	As an effective boundary lubricant	0.010–0.080	[88]
Cyclic brush copolymer	Form a dense and highly hydrated “brush” layer	0.010–0.060	[89]
Catechol grafted chitosan	Recruit glycoproteins, HA, and lipids to provide lubrication	0.030	[90]
Mimics of lubricin	Promote interactions with the articular surface and synovial fluid	0.050	[91]
Peptide‐modified molecule	The attachment and full coverage of molecules was critical to supporting lubrication	0.190	[92]
HA based lubricants
HA/Phosphorylcholine Polymer	Excellent hydration lubrication	0.020–0.030	[93]
HA derivative with amphiphilic features	Via longer residence time in the joint than in native HA	0.014	[94]
HA reinforced with graphene oxide	Form a solid lubrication film	—	[58]
HA/PA@Lipo‐GA	Form a boundary lubricating layer	0.036	[95]
HA/PM		0.008	[58]
HA/PA + HA/PM		0.005	[58]
Hyaluronan (HA)‐phosphatidylcholine (PC) complexes, especially HA–HSPC	The formation of a stable boundary layer and hydration lubrication	0.001	[96]
Engineered triblock bottlebrush (BB) polymer; synergistic system with hyaluronic acid (HA)	A robust hydrated boundary layer and hydration lubrication	0.001–0.002	[97]
Enzymatically crosslinked silk fibroin‐hyaluronic acid (SF‐HA) composite hydrogels	Hydration lubrication, and boundary lubrication	—	[46]
PC based lubricants
poly[2‐(methacryloyloxy) ethyl phosphorylcholine]	Hydration lubrication mechanism	0.001–0.003	[82]
MSNs‐NH2@PMPC(PMPC polymer brushes‐grafted MSNs)	Hydration lubrication mechanism	0.020	[59]
PMPC brush grafted onto the backbone of PHEA(mimLUB)	excellent hydration boundary lubrication	0.028	[98]
Lubricants with dual polymer synergism
A HA backbone grafted with poly(2‐acrylamide‐2‐methylpropanesulfonic acid) (PAMPS) and PMPC	Form a stable hydrated layer on cartilage surfaces	0.005	[60]
Other types of lubricants
Zwitterionic polymer‐grafted Mesoporous silica nanoparticle	Hydration lubrication mechanism	0.045	[99]
Poly (3‐sulfopropyl methacrylate potassium salt)‐grafted mesoporous Silica nanoparticle	The formation of tenacious hydration layers surrounding negative charges	0.065	[100]
Chitosan nanoparticles‐based Biomimetic lubricant	Form an effective hydration layer surrounding the negatively charged SO3 − groups	0.010	[59]
Poly (3‐sulfopropylmethacrylate potassium salt) brushes grafted poly(N‐isopropylacrylamide) microgel	A good water‐based hydration lubrication.A compact adsorbed coating to contribute to the lubrication	0.005–0.015	[101]
2‐methylacryloyloxyethyl phosphorylcholine decorated methacrylate anhydride‐hyaluronic acid drug delivery nanosphere	Form a hydrated lubricating layer	—	[102]
Poly (2‐methacryloyloxyethyl phosphorylcholine)‐grafted mesoporous silica nanosphere	The formation of a tenacious hydration layer surrounding the zwitterionic charges of polymer brushes	0.010	[56]
Cyclic polymer c‐P(HEMA) as the core template and SBMA, DMAEMA as brushes	hydration lubrication, super‐lubrication of cyclic brushes, and steric stability of cyclic topology	0.017	[54]
Hairy polyelectrolyte brushes‐grafted thermosensitive microgels	Hydration, lubrication, and the elastic support of microgels	0.001–0.010	[79]
Nanoassemblies of tissue‐reactive polyoxazoline graft‐copolymers	superlubrication of cyclic brushes and steric stability of cyclic topology	0.001–0.010	[27]
Polypept(o)ide‐based core–shell bottlebrush polymers	Boundry lubrication	< 0.010	[89]

4.1. Phosphatidylcholine‐Based Proteoglycan Biomimetic Polymer Brushes

Phosphatidylcholine (PC)‐based polymer brushes primarily exploit hydration lubrication through zwitterionic head groups, mimicking phospholipid‐mediated lubrication in native joints. Phosphatidylcholine has attracted extensive attention due to its outstanding hydration lubrication properties. Its molecular structure consists of two hydrophobic fatty acyl tails and a zwitterionic phosphatidylcholine head group, making it an effective boundary lubricant for cartilage [59]. As early as 1984, Hills and Butler proposed a boundary lubrication model in which the zwitterionic head groups of phospholipids adsorb onto the negatively charged cartilage surface, while the hydrophobic tails extend outward and dissipate energy under shear [78]. However, subsequent studies revealed that a more effective lubrication mechanism involves sliding between hydrated PC head groups, where friction dissipation occurs within interfacial water layers, resulting in significantly lower friction coefficients [98].

Accordingly, phosphatidylcholine‐inspired polymer brushes are designed to reproduce this hydration lubrication mechanism. Among them, poly(2‐methacryloyloxyethyl phosphorylcholine) (PMPC) (Figure 6) exhibits remarkable lubrication performance, characterized by ultralow friction coefficients, excellent wear resistance, and high biocompatibility [103]. Early work demonstrated that PMPC polymer brushes can achieve friction coefficients approaching those of natural synovial joints. As a polyzwitterion, PMPC can maintain extremely low friction (μ ≈ 0.001) even under high pressure (> 5 MPa), owing to the strong hydration capability of its phosphorylcholine groups [33].

FIGURE 6.

Schematic diagram of the lubrican structure existing in the synovial fluid of mammalian joints (A) and schematic diagram of a bottle‐brush‐shaped polymer simulating lubricin (B,C). The figures were adopted with permission from the study by Banquy et al. [110] Copyright 2014 American Chemical Society.

Recent studies further expanded this strategy by integrating PMPC brushes with nanocarriers. For example, PMPC‐grafted mesoporous silica nanorods were developed to form stable, load‐bearing hydration layers under shear, significantly reducing cartilage friction and slowing OA progression [56]. Similarly, PMPC‐modified nanoparticles exhibit lower friction coefficients compared with unmodified counterparts on artificial joint surfaces. In another approach, atom transfer radical polymerization (ATRP) was employed to graft PMPC side chains onto a poly(2‐hydroxyethyl methacrylate) (PHEMA) backbone, yielding a biomimetic molecular brush (mimLUB) that combines hydration lubrication with self‐assembled network formation [104].

4.2. Hyaluronic Acid‐Based Proteoglycan‐Mimetic Polymer Brushes

Hyaluronic acid (HA)‐based polymer brushes primarily focus on enhancing viscoelastic lubrication and cartilage interaction, mimicking the HA‐centered supramolecular network in synovial fluid. HA is a negatively charged, non‐sulfated glycosaminoglycan widely distributed in synovial fluid and cartilage extracellular matrix [45, 46]. Its excellent viscoelasticity contributes to load distribution, surface separation, and friction reduction in joints [47, 48]. In addition to its mechanical role, HA exerts biological effects through CD44‐mediated signaling, contributing to anti‐inflammatory and chondroprotective functions [49, 50, 96, 105]. However, surface force balance studies indicate that HA alone exhibits relatively weak boundary lubrication performance, highlighting the necessity of structural modification or synergistic interactions [27, 67, 97, 106].

To address this limitation, various HA‐based bottle‐brush systems have been developed. For example, ABA triblock copolymers containing phosphorylcholine side chains and cationic terminal segments enable strong electrostatic binding to HA and rapid adsorption onto cartilage surfaces, significantly improving lubrication and delaying degeneration compared with direct HA injection [107]. Moreover, hybrid systems combining HA with polymer brushes or lipid components have demonstrated enhanced lubrication performance. Interactions between HA and phospholipid vesicles (SUVs) significantly reduce friction, indicating the importance of synergistic molecular interactions [95]. Mao and Ren's group developed HA‐based nanopolymer brushes with strong affinity for cartilage proteins, forming stable hydrated layers and achieving friction coefficients lower than those of natural lubricants [19]. Other strategies include grafting HA onto synthetic polymers (e.g., HA/PA systems) and integrating functional agents such as antioxidants. For instance, HA/PA@Lipo‐GA combines lubrication with ROS scavenging and anti‐inflammatory activity, showing therapeutic efficacy in OA animal models [46, 54].

Overall, HA‐based polymer brushes not only enhance lubrication through viscoelastic and hydration mechanisms but also provide a versatile platform for biological interaction and multifunctional therapy in osteoarthritis.

4.3. Other Proteoglycan‐Mimetic Polymer Brush Systems

Beyond HA‐ and PC‐based systems, a variety of alternative polymer brush architectures have been developed to further optimize specific design principles, such as responsiveness, adhesion, and structural stability [59, 88, 89, 108]. For example, pH‐responsive cyclic brush polymers based on sulfobetaine methacrylate (SBMA) exhibit ultralow friction (μ ≈ 0.017), benefiting from stable hydration layers and unique cyclic topology [60]. Similarly, PNIPAM‐based microgels grafted with sulfopropyl methacrylate (PSPMK) utilize negatively charged hydration layers to reduce joint friction [59].

To enhance cartilage adhesion, polymer brushes incorporating functional groups such as thiols or aldehydes have been developed. For instance, PAA–PEG‐based brushes and polyglutamic acid‐based systems with benzaldehyde groups exhibit improved surface anchoring and sustained lubrication [88, 89, 108]. In addition, proteoglycan‐mimetic systems incorporating glycosaminoglycan side chains have been reported. BPG10, composed of a PAA backbone grafted with chondroitin sulfate chains, can accumulate in the pericellular matrix (PCM), increase fixed charge density, and stabilize degraded proteoglycans, thereby enhancing cartilage mechanical properties [61]. Furthermore, core–shell bottle‐brush polymers with hierarchical structures have been designed to integrate lubrication with drug delivery capabilities. For example, polylysine‐based core–shell systems exhibit excellent biocompatibility, structural stability, and controlled drug release, providing multifunctional therapeutic potential [109].

Despite their structural diversity, these systems share common biomimetic features, including bottle‐brush architecture, hydration‐mediated lubrication, and effective surface interaction, which align with the fundamental design principles of proteoglycan‐inspired lubrication.

5. Dual‐Polymer Synergistic Strategies

To overcome the limitations of single‐component systems, dual‐polymer strategies have emerged as an advanced design approach for proteoglycan‐mimetic polymer brushes. While most existing studies focus on single‐component brushes for lubrication and osteoarthritis (OA) therapy, accumulating evidence indicates that synergistic integration of multiple polymer components can achieve superior performance in both lubrication and cartilage repair.

Dual‐polymer systems are typically designed to integrate complementary functionalities, such as hydration lubrication, viscoelasticity, and interfacial interactions. For example, a hyaluronic acid (HA) backbone dually grafted with poly(2‐acrylamido‐2‐methylpropanesulfonic acid) (PAMPS) and poly(2‐methacryloyloxyethyl phosphorylcholine) (PMPC) has been developed to simultaneously mimic the hydration lubrication of proteoglycans and the amphiphilic behavior of phospholipids. Molecular dynamics simulations and experimental results demonstrated that this dual‐brush system forms a stable and robust hydration layer on cartilage surfaces. As a result, the friction coefficient of osteoarthritic cartilage was reduced to 0.00522 ± 0.0007, approaching the range of healthy cartilage (0.001–0.03). In addition, intra‐articular retention was significantly prolonged compared with single‐brush systems, indicating improved stability and durability in the joint environment. More importantly, dual‐polymer systems can overcome a key limitation of single‐component materials—namely, their inability to simultaneously address lubrication deficiency and disease progression. While single polymer brushes primarily delay cartilage degeneration, the synergistic integration of multiple functional components enables more comprehensive therapeutic effects, including enhanced cartilage protection and regeneration [58].

From a design perspective, this synergistic strategy highlights the importance of combining multiple biomimetic elements—such as bottle‐brush architecture, hydration lubrication, and surface interaction—within a single platform. Such chemical complementarity and functional integration provide a promising route toward achieving not only friction reduction but also structural restoration of cartilage. Accordingly, dual‐polymer brush systems represent a significant advancement beyond conventional lubrication strategies and may establish a new paradigm for early‐stage OA intervention. The typical progress of lubrication‐enhancing biomaterials for osteoarthritis therapy is summarized in Figure 7.

FIGURE 7.

Typical progress of nature‐inspired lubrication biomaterials for osteoarthritis therapy. Figures are adapted with permission from Xie R J et al. [58], Copyright 2021, The Author(s), under exclusive licence to Springer Nature Limited; Zhang M et al. [60], Copyright The Royal Society of Chemistry 2023; Lin Y G et al. [111], Copyright 2026 The Author(s). Advanced Science published by Wiley‐VCH GmbH. Licensed under CC‐BY 4.0; Yang H et al. [112], Copyright 2023 Elsevier Inc. All rights reserved; Chen H et al. [56], Copyright 2020 Elsevier Ltd; Yang L M et al. [104], Copyright 2023 Elsevier Ltd. All rights reserved; Yan Y F et al. [100], Copyright 2018 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim; Yan R Y et al. [54], Copyright 2024, American Chemical Society; Gong C Y et al. [113], Copyright 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies; Yang L M et al. [114], Copyright 2022 Elsevier Inc. All rights reserved.

6. Summary and Outlook

Inspired by the bottle‐brush architecture and superlubricious function of native proteoglycans, biomimetic polymer brush lubricants have been extensively developed to replicate both the structure and lubrication mechanisms of endogenous synovial constituents. These systems effectively address the compositional uniformity and functional limitations of conventional clinical lubricants while improving lubrication performance and therapeutic potential. By emulating hydration lubrication, proteoglycan‐mimetic polymer brushes can achieve friction coefficients comparable to–or even lower than‐those of natural articular cartilage. Through replenishing depleted proteoglycans and restoring interfacial hydration layers, they reduce cartilage friction and wear, thereby alleviating osteoarthritis (OA)‐associated degeneration. In addition, their tunable structure, controllable conformation, and modifiable surface properties enable further optimization of lubrication efficiency. Collectively, these features highlight polymer brushes as highly promising candidates for lubrication‐based OA therapy [115, 116].

However, despite these advances, several critical challenges still hinder their clinical translation. Among them, long‐term stability, robust surface anchoring, and durability in inflammatory joint environments are particularly important translational barriers. The joint cavity is a highly dynamic environment characterized by continuous mechanical loading, shear stress, synovial fluid turnover, and lymphatic clearance. Therefore, polymer brushes with insufficient cartilage affinity or weak surface anchoring may be rapidly removed from cartilage surfaces, resulting in inadequate residence time, unstable lubrication layers, and reduced therapeutic efficacy. In addition, the inflamed OA microenvironment contains elevated levels of inflammatory cytokines, reactive oxygen species, proteolytic enzymes, and catabolic mediators, which may accelerate polymer degradation, disrupt brush conformation, weaken interfacial hydration layers, and compromise sustained lubrication performance [117, 118, 119]. Therefore, enhancing cartilage‐specific anchoring, mechanical robustness, and resistance to inflammatory degradation is essential for advancing proteoglycan‐mimetic polymer brushes from experimental lubricants toward clinically applicable OA therapies with durable performance.

Biosafety and in vivo biodegradation are also essential considerations for clinical application. Although many proteoglycan‐mimetic polymer brushes have shown favorable cytocompatibility and tissue compatibility in preclinical studies, their long‐term biological fate within the joint cavity remains insufficiently understood. Key issues include degradation kinetics, clearance pathways, potential accumulation of polymer fragments, immunogenicity, synovial irritation, local and systemic toxicity, and the safety of degradation products. In the inflammatory OA microenvironment, oxidative stress and enzymatic activity may further induce structural degradation or functional attenuation of polymer brushes over time. Therefore, systematic evaluation of long‐term biosafety, biodegradation behavior, pharmacokinetics, and local tissue responses is required before clinical translation.

At a more fundamental level, the molecular mechanisms governing brush–cartilage interactions and structure–lubrication relationships remain incompletely understood. Moreover, the development of stimuli‐responsive, particularly multi‐responsive, polymer brush systems is still in its early stages. From a translational perspective, scalable manufacturing, batch‐to‐batch reproducibility, sterilization compatibility, storage stability, cost control, clinically relevant dosing regimens, and comparison with existing intra‐articular therapies should also be carefully addressed. In addition, the lack of real‐time, imaging‐based monitoring strategies in OA further limits the evaluation of therapeutic outcomes. Although nanomaterials have been widely explored in biomedical imaging and therapy, their integration with polymer brush systems for OA monitoring and treatment remains underdeveloped.

Looking forward, several directions may accelerate the advancement of proteoglycan‐mimetic polymer brushes. Future studies should prioritize cartilage‐specific anchoring strategies, mechanically robust brush architectures, and inflammation‐resistant polymer chemistries to achieve long‐term retention and durable lubrication under pathological joint conditions. In parallel, biosafety‐oriented material design, controllable in vivo biodegradation, reliable clearance, and systematic toxicity evaluation will be crucial for clinical translation. The development of multifunctional systems that integrate lubrication, anti‐inflammatory activity, and tissue regeneration may further contribute to disease‐modifying effects. In addition, incorporating stimuli‐responsive features may enable dynamic adaptation to the joint microenvironment. The integration of imaging modalities—such as X‐ray, near‐infrared, and ultrasound—into polymer brush platforms could further enable real‐time tracking of their intra‐articular behavior, thereby facilitating mechanistic understanding and therapeutic optimization.

In summary, proteoglycan‐mimetic polymer brushes represent a promising and rapidly evolving strategy for OA intervention. With continued advances in material design, surface anchoring, long‐term durability, biosafety and biodegradation evaluation, and translational development, these systems are expected to progress from experimental platforms toward clinically viable, disease‐modifying therapies for osteoarthritis.

Author Contributions

F.C. conceived the review, collected and analyzed the literature, prepared the figures, and wrote the original draft of the manuscript. L.Z. assisted in drafting the manuscript. Y.Z. contributed to literature sorting. C.Q. contributed to manuscript revision. Y.L. provided conceptual guidance, supervised the study, and critically revised the manuscript. All authors read and approved the final version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.