Conventional DEX-liposomes show strong efficacy in experimental arthritis, with PEG-free design minimizing immunogenicity and hypersensitivity risks (Avnir et al., 2008[10]).

Anderson and the team of researchers (Anderson et al., 2010[6]) evaluated the efficacy of intravenous (i.v.) DEX-Lips phosphate (DxM-P) compared with free DxM-P in rats with established adjuvant arthritis (AA). Treatment with non-PEGylated liposomes produced significant and long-lasting suppression of inflammation and joint swelling at 3-10 times lower doses than the free glucocorticoid. A short 3-day course not only reduced arthritis scores but also prevented nearly 80 % of flare-ups after therapy withdrawal, demonstrating a depot-like effect. Encapsulation enabled a dose reduction of 3-10-fold, with drug levels remaining significantly higher in plasma, synovial membrane, spleen, and liver for at least 48 hours post-injection. Short-term i.v. treatment with liposomal DxM-P (3 × 1 mg/kg on Days 14-16 of AA) nearly normalized arthritis scores and paw volume (Figure 5a, b(Fig. 5); Reference in Figure 5: Anderson et al., 2010[6]).

By Day 28, two weeks after initiation, the formulation maintained a 54 % reduction in arthritis score and a 73 % reduction in paw swelling. In contrast, the same dosage of free DxM-P produced only transient improvements, with rapid rebound after treatment cessation. PBS-liposomes were ineffective and occasionally worsened symptoms. The area under the curve (AUC) further demonstrated the superiority of liposomal encapsulation: arthritis score AUC was reduced by 54 % (versus 19 % with free drug), and paw swelling AUC by 74 % (versus 36 % with free drug; Figure 5a, b(Fig. 5)). Despite a temporary drop in body weight (Figure 5c(Fig. 5)), treatment was well tolerated, and animals quickly regained normal activity (Anderson et al., 2010[6]).

These findings were consistently reproduced in independent experiments, validating the robustness of the results. The formulation selectively accumulated in inflamed joints, spleen, and liver, where it acted as a localized drug depot. This site-specific retention prolonged therapeutic activity, limited systemic exposure, preserved joint integrity by reducing cartilage and bone erosion, and suppressed pro-inflammatory cytokines such as IL-1β and IL-6.

Rauchhaus and colleagues developed liposomes using DPPC, DPPG, and cholesterol (50:10:40 mol%) via lipid film extrusion for RA and related inflammatory disorders. Encapsulation of DEX phosphate (DXM-P) resulted in a more sustained anti-inflammatory effect than the free drug. Remarkably, a single 4 mg/kg dose of liposomal DXM-P provided therapeutic benefit with fewer glucocorticoid side effects, even after drug clearance by day 2, suggesting an improved therapeutic window (Rauchhaus et al., 2009[61]). Although conventional liposomes lack PEGylated carriers' extended circulation, they balance efficacy and safety, avoid PEG-associated immune responses, and still achieve notable anti-inflammatory activity.

Conventional liposomes are attractive drug carriers but face two major limitations. Their circulation time in the blood is short due to rapid clearance by the reticuloendothelial system (RES), and their structural stability under physiological conditions is often insufficient, resulting in premature drug leakage. Surface modification with polyethylene glycol (PEG) provides a hydrophilic “stealth” layer that minimizes RES recognition and prolongs systemic circulation, thereby improving drug bioavailability (Patel et al., 2024[55]).

To improve membrane robustness, lipid polymerization within the bilayer has been developed, enhancing structural integrity and reducing premature leakage. More recently, the combination of PEGylation with polymerized lipid systems has yielded polymerized stealth liposomes, which integrate prolonged circulation with improved stability (Makharadze et al., 2025[46]; Hofkens et al., 2011[27]). These advanced carriers show promise for achieving sustained therapeutic activity and reducing off-target effects, making them particularly relevant for the treatment of chronic inflammatory diseases such as RA (Ferreira-Silva et al., 2021[22]).

In arthritic animal models, such PEGylated liposomes carrying anti-inflammatory agents like DEX not only demonstrated prolonged presence in the circulation but also preferentially accumulated in inflamed joints, suppressing pro-inflammatory cytokines such as TNF-α and IL-1β and significantly reducing joint swelling and disease progression (Prasad et al., 2015[58]).

Beyond PEGylation, researchers have explored (Wang et al., 2020[78]) polymer-stabilized stealth liposomes to improve stability and therapeutic durability. Wang et al. developed polymerized stealth DEX Liposomes using 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC) and DSPE-PEG2000 via thin-film hydration. In this system, DC8,9PC molecules were UV-crosslinked within the bilayer, enhancing structural integrity, while surface PEG chains provided a stealth coating to extend circulation. Polymerized liposomes exhibited excellent stability, prolonged circulation, and efficient cellular uptake with minimal toxicity.

In arthritic rat models, these polymerized liposomes showed superior therapeutic efficacy compared to free dexamethasone, with greater reductions in joint inflammation, paw swelling, and pro-inflammatory cytokines such as TNF-α and IL-1β. Overall, these findings suggest improved therapeutic outcomes due to enhanced stability, sustained drug release, and better accumulation at inflamed sites. However, translation requires further validation of safety, reproducibility, and long-term outcomes (Wang et al., 2020[78]).

In RA, intravenous delivery of nanocarriers often results in drug loss and poor targeting, while intra-articular (IA) delivery improves local action and reduces systemic side effects but suffers from rapid clearance and frequent injections (Song et al., 2022[70]). Liposomal encapsulation of DEX overcomes these limitations by protecting the drug from enzymatic degradation, prolonging IA half-life, and reducing injection frequency, thereby lowering the risks of joint infection and tissue damage. Early studies demonstrated that DEX-Lips (dexamethasone palmitate) achieved superior joint retention and anti-inflammatory efficacy compared to microcrystalline steroids, with larger vesicles (~750 nm vs. 160 nm) further enhancing synovial retention. Notably, DEX-Lips avoided systemic cortisol suppression and showed a safer profile than free DEX in RA models, with minimal effects on body weight, blood glucose, and hematological parameters (Jia et al., 2018[34]). These findings underscore its potential as an effective strategy to improve IA retention while minimizing systemic exposure.

Kulikov et al. developed DEX-Lips (vesicle size ~86 nm; drug concentration 2.2 mg/mL) for intra-articular use in a rat arthritis model. Compared with free DEX solution at the same dose, the liposomal formulation produced greater improvements in both macroscopic and microscopic indicators of joint inflammation, demonstrating superior therapeutic efficacy for arthritis management (Kulikov et al., 2021[40]). Chondroitin sulfate (ChS) protects cartilage by preventing IL-1β-induced apoptosis and promoting regeneration and repair of cartilage tissue. Combining anti-inflammatory action with cartilage repair provides an effective approach for RA therapy. To achieve this, DEX liposomes incorporating ChS and gelatin offer significant therapeutic potential (Siddiqui et al., 2024[69]; Wang et al., 2020[82]).

Zhang and colleagues developed a hyaluronic acid-modified liposomal depot (HA-Lipo@G/D) encapsulating a dexamethasone-loaded nanogel, enabling CD44-mediated targeting and enhanced retention in inflamed joints (Zhang et al., 2025[98]). In arthritis models, it showed superior efficacy over free drug, significantly reducing inflammation, joint swelling, and pro-inflammatory cytokines while improving cartilage preservation and IL-10 levels. Overall, this system combines targeted delivery with sustained release for improved therapeutic outcomes, though challenges in clinical translation and long-term safety remain (Zhang et al., 2025[98]).

Wang and team of researchers developed sialic acid-decorated DEX-Lips palmitate (DP-SALs) to target peripheral blood neutrophils, which naturally migrate to inflamed joints in RA. They tested three sizes (300, 150, and 75 nm) and found that particle size strongly influenced uptake, migration, and therapeutic effect. Sialic acid helped neutrophils selectively carry DP-SALs to inflamed sites. Large liposomes had higher drug loading but impaired neutrophil function, while small DP-SALs preserved neutrophil activity, localized efficiently in arthritic joints, and showed superior efficacy. In rats, small DP-SALs reduced swelling, joint damage, and pro-inflammatory cytokines (TNF-α, IL-1β), offering the best targeted and long-lasting RA therapy (Wang et al., 2021[79]).

For localized therapy in mono- or oligo-articular RA, intra-articular liposomal injections sustain joint drug levels but are limited by short action and systemic effects. Transdermal delivery offers safer, steady dosing, though hindered by skin barriers. Zhao and team of investigators (Zhao et al., 2022[99]) synthesized a transdermal dextran sulfate (DS)-modified (DEX)-loaded flexible liposome hydrogel (DS-FLs/DEX hydrogel) and systematically verified its transdermal effectiveness, macrophage targeting, and anti-inflammatory property. The DS-FLs/DEX hydrogel showed excellent biocompatibility, long-term drug release, and targeted uptake by lipopolysaccharide (LPS)-activated macrophages. In vivo imaging demonstrated significantly higher skin accumulation, with fluorescence intensity reaching 4,665 ± 324 for DS-FLs/DEX, compared to 2,623 ± 431 for DS-RLs/DEX and 2,545 ± 226 for free drug, indicating ~1.7-1.8-fold higher permeability (Figure 6A-D(Fig. 6); Reference in Figure 6: Zhao et al., 2022[99]). Therapeutically, both hydrogels reduced arthritis severity, as seen by decreased clinical scores and paw thickness (Figure 6E, F(Fig. 6)). DS-FLs/DEX showed superior efficacy, with paw thickness nearly returning to normal levels, consistent with improved clinical scores. Macroscopic observations of hind limbs also confirmed reduced inflammation (Figure 6G(Fig. 6)). Overall, the enhanced effect of DS-FLs/DEX is attributed to its higher deformability and improved transdermal delivery to inflamed joints (Zhao et al., 2022[99]).

Peptide-targeted liposomal systems have gained attention for their ability to enhance drug selectivity and efficacy in RA. One of the most widely studied approaches uses the RGD (arginine-glycine-aspartic acid) peptide, a well-characterized integrin-binding motif, to functionalize PEGylated liposomes for targeting αvβ3 integrins on angiogenic endothelial cells within inflamed joints. These RGD-modified liposomes demonstrated efficient binding and internalization by vascular endothelial cells in vitro and preferential accumulation at inflamed sites in vivo, as confirmed by intravital microscopy. Importantly, encapsulation of DEX phosphate in RGD-PEG liposomes resulted in sustained suppression of arthritis progression in the adjuvant-induced arthritis model, providing superior outcomes compared to free drug and non-targeted liposomes (Koning et al., 2006[38]).

Building on this concept, Meka and the team of investigators engineered a peptide-directed liposomal delivery system for DEX (DEX-LPs-Target) for enhanced therapeutic efficacy in RA. A peptide sequence, CKPFDRALC (designated ART-2), demonstrated selective accumulation in arthritic rat joints and strong affinity for endothelial cells (Meka et al., 2019[47]).

Therapeutic efficacy was tested in the collagen-induced arthritis (CIA) model in mice, wherein peptide-directed DEX-LPs showed significantly greater anti-arthritic activity compared with free DEX and control, non-targeted liposomes. Together, RGD- and ART-2-modified liposomes illustrate the promise of peptide-guided targeting in RA, offering improved drug delivery to diseased tissues while reducing systemic toxicity (Meka et al., 2019[47]).

However, translation to clinical settings requires addressing potential drawbacks, including the immunogenicity of peptide ligands, the stability of peptide-lipid conjugation, and the scalability of production. Long-term safety and efficacy studies remain essential to validate their promise as next-generation RA therapeutics.

An alternative strategy to deliver DEX to inflamed joints is to use nanoparticles that interact with albumin. Albumin is abundant, biocompatible, has a long half-life, and naturally accumulates in inflamed tissues. Instead of directly formulating DEX with albumin, Wang et al. (2024) formulated liposomes modified with an albumin-binding domain (ABD), a 46-residue peptide derived from streptococcal protein G. This allows the liposomes to capture endogenous albumin in circulation, extending blood half-life and enhancing drug accumulation at inflamed sites. ABD functionalization improved albumin binding, cellular uptake, and in vivo targeting. In rats with adjuvant-induced arthritis, ABD-Lip/DEX accumulated at inflamed joints, reduced swelling, and lowered TNF-α and IL-1β levels, without notable toxicity or hematological side effects.

Single-drug therapies often inadequately control RA progression. While DEX effectively suppresses inflammation, its long-term use is constrained by systemic toxicity. Luteolin (LUT), a natural flavonoid with antioxidant and NF-κB inhibitory activity, provides complementary benefits. However, its poor solubility and low bioavailability hinder therapeutic potential, highlighting the need for advanced delivery strategies.

To address these challenges, a dual-drug delivery platform based on hyaluronic acid (HA)-modified liposomes, termed hyalurosomes, was engineered by Zewail and colleagues (Zewail et al., 2025[94]) to co-encapsulate DEX and LUT. This strategy integrates the potent anti-inflammatory effects of DEX with the antioxidant and NF-κB-modulating activity of LUT. Surface modification with HA improves accumulation in inflamed synovial tissue via CD44 receptor targeting while prolonging intra-articular retention. Sustained co-release of both agents enhances local efficacy and minimizes systemic exposure (Zewail et al., 2025[94]). The formulation demonstrated high drug encapsulation efficiency (~93 % for DEX and ~81 % for LUT) and controlled release, with less than 50 % of either drug released within 24 h. In adjuvant-induced arthritis rats, DEX-LUT hyalurosomes significantly reduced inflammatory and oxidative markers, including TNF-α, IL-1, MMP-3, and MDA, while enhancing NRF2 expression. These biochemical outcomes confirmed the synergistic suppression of inflammatory and oxidative pathways. Joint diameters were recorded on days 0, 3, 7, and 14. Notably, the DEX-LUT hyalurosome group showed no statistical difference from the negative control, suggesting near-complete restoration of joint function. Morphological assessment at day 14 revealed that while blank hyalurosomes and single-drug liposomes improved joint condition, the dual-drug formulation provided the most pronounced recovery, with outcomes almost identical to healthy controls.

Co-delivery of DEX and LUT via hyalurosomes represents a rational therapeutic approach for RA. By combining anti-inflammatory and antioxidant activities with HA-mediated targeting and sustained release, this system achieves superior efficacy and safety compared to single-agent liposomal formulations. Future studies should focus on optimizing dosing strategies, evaluating long-term safety, and exploring translation to human clinical settings. Moreover, extending this co-delivery concept to other natural compounds or DMARDs may broaden therapeutic potential and establish dual-drug liposomes as a versatile platform for next-generation RA therapy (Zewail et al., 2025[94]).

Cholesterol is traditionally incorporated into liposomes to increase bilayer rigidity and extend circulation. However, prolonged exposure can activate complement protein C3, leading to immune clearance and inflammation (Inglut et al., 2020[33]). These limitations have motivated exploration of safer substitutes that preserve structural stability while adding therapeutic benefits. One promising candidate is ginsenoside compound K (CK), a rare ginseng metabolite with a sterol-like structure. CK demonstrates anti-inflammatory, anticancer, and immunomodulatory activity and can stabilize lipid bilayers similar to cholesterol. In RA, it reduces synovial inflammation, inhibits T-cell activation, and suppresses glycolysis through NF-κB/HIF-1α signaling. Nonetheless, CK suffers from poor solubility, low bioavailability, and limited accumulation in joints, restricting its clinical use (Hong et al., 2019[28]).

RA pathology involves synovial inflammation, angiogenesis, and cartilage damage, producing vascular hyperpermeability akin to the tumor EPR effect. Leveraging this feature, Zhang and colleagues (Zhang et al., 2025[97]) designed ginsenoside-based liposomes using CK as both a cholesterol substitute and therapeutic agent, co-loaded with DEX for synergistic benefit. The resulting CK + DEX@Lipo system was evaluated against conventional cholesterol liposomes (Cho@Lipo) in vitro and in vivo. Figure 7(Fig. 7) (Reference in Figure 7: Zhang et al., 2025[97]) illustrates the biodistribution. In vivo fluorescence imaging showed that DiR-labeled liposomes preferentially accumulated in inflamed paws of CIA mice, but not in healthy joints (Figure 7A(Fig. 7)). Quantitative analysis revealed ~1.5-fold higher fluorescence intensity for CK@Lipo compared to Cho@Lipo (Figure 7B(Fig. 7)). At 48 hours, CK@Lipo demonstrated enhanced joint localization with reduced off-target organ uptake (Figure 7C(Fig. 7)), likely mediated by ginsenoside-binding receptors. Therapeutic outcomes confirmed CK's advantage. As shown in Figure 7D and E(Fig. 7), PBS-treated mice exhibited severe swelling and progression of arthritis, whereas Cho@Lipo provided negligible benefit. CK@Lipo significantly lowered swelling and arthritis indices, confirming CK's dual stabilizing and therapeutic function. Free DEX and DEX@Lipo improved symptoms, but the most profound improvement occurred with CK + DEX@Lipo, which nearly restored normal joint morphology. Cytokine analysis (Figure 7F(Fig. 7)) showed that CK@Lipo reduced TNF-α, while CK + DEX@Lipo produced the strongest suppression. Histopathology (Figure 7G(Fig. 7)) revealed that only the CK + DEX formulation prevented cartilage erosion, synovial hyperplasia, and immune infiltration, closely resembling healthy tissue. Mechanistically, CK integrates into liposomal bilayers to confer stability and therapeutic efficacy, while DEX broadly suppresses cytokine production. Together, they synergize to control RA progression. Replacing cholesterol with CK represents a paradigm shift in liposome design, transforming a structural component into a multifunctional therapeutic element. Although clinical translation requires overcoming manufacturing, pharmacokinetic, and safety hurdles, CK-based liposomes hold promise as next-generation platforms for RA and other immune, metabolic, and oncologic diseases.

Cell membrane-based biomimetic carriers offer biocompatibility, immune evasion, and targeted delivery, showing therapeutic potential in cancer, infections, and autoimmune diseases (Xiao et al., 2022[89]; Liu et al., 2023[42]). Among these, mesenchymal stem cell (MSC) membranes are especially attractive due to low immunogenicity, easy expansion, and innate homing to inflamed tissues (Castro Nava et al., 2023[14]). Their surface proteins, including chemokine receptors (CXCR4, CXCR1, CCR2) and adhesion molecules (VCAM-1, VLA-4, LFA-1), enhance migration (Cui et al., 2024[18]).

Building on this, Ma et al. developed MSC-membrane-coated liposomes encapsulating DEX (DEX-MSCsomes) for RA. In a CIA mouse model, DEX-MSCsomes showed superior anti-inflammatory effects, reduced swelling, and preserved cartilage compared with free DEX and conventional DEX-liposomes (Ma et al., 2024[44]).

DEX-MSC-somes show promising targeting and therapeutic effects in RA, but key challenges include standardizing membrane isolation, scalable production, and ensuring long-term safety and stability. Optimizing drug loading, release, and pharmacokinetics remains crucial. Future directions involve co-delivery, patient-specific membranes, stimuli-responsive release, and AI-guided monitoring, with potential to expand applications to other autoimmune and inflammatory disorders.

Stimuli-responsive liposomes represent next-generation strategies for RA therapy. Unlike conventional carriers, they remain intact under physiological conditions but undergo controlled activation in response to pathological cues, thereby enabling localized drug release and reducing systemic toxicity (Zhang et al., 2022[96]). In RA joints, acidic pH (6.4-6.6), high levels of reactive oxygen species (ROS), and overexpression of matrix metalloproteinases (MMP-1, MMP-3, MMP-13) provide exploitable triggers. Liposomes engineered with pH-sensitive lipids or ROS-cleavable linkers, such as thioketals and boronates, enable selective release. Recent designs integrate stimulus-responsiveness with active targeting or depot strategies to further enhance therapeutic precision (Kondo et al., 2023[37]).

Song and a team of researchers introduced a dual-functional liposome (DEX@FA-ROS-Lips) incorporating ROS-cleavable lipids and folic acid ligands for macrophage targeting. This system enabled receptor-mediated uptake followed by ROS-triggered drug release, effectively suppressing the iRhom2/TNF-α/BAFF axis and reducing inflammation in arthritis models, while maintaining good hemocompatibility (Song et al., 2021[71]). Similarly, Ni and colleagues developed ROS-sensitive, folate-conjugated nanoparticles targeting both macrophages and fibroblast-like synoviocytes, achieving potent suppression of synovial hyperplasia (Ni et al., 2020[52]). Together, these approaches demonstrate the therapeutic promise of multifunctional, stimuli-responsive liposomes. Despite challenges in stability, scalability, and clinical validation, these “smart” carriers hold strong potential to advance corticosteroid-based RA therapy.

Antigen-specific immunotherapy represents a highly promising strategy for autoimmune diseases, as it enables selective suppression of pathogenic immune responses while preserving normal immune function (Page et al., 2021[54]). Central to this approach are tolerogenic dendritic cells (tolDCs), which suppress pro-inflammatory Th1 and Th17 subsets while promoting the expansion of regulatory T cells (Tregs, Tr1s) (Domogalla et al., 2017[20]). This immunological reprogramming restores tolerance by reducing cytokines such as IL-12 and TNF-α and enhancing IL-10 and TGF-β. Importantly, tolDCs can be engineered with disease-specific antigens, offering precise modulation without broad immunosuppression. While early clinical studies in RA have produced encouraging findings (Willekens et al., 2019[87]; Phillips et al., 2019[56]), their broader application is constrained by high costs, variability, and the need for specialized production facilities.

Nanoparticles, particularly liposomes, are being investigated as scalable, cost-effective alternatives. Liposomes are biocompatible vesicles that can encapsulate antigens and drugs while directing immune responses. For example, anionic DSPG (2-distearoyl-sn-glycero-3-phosphoglycerol) liposomes enhance antigen uptake by dendritic cells and stimulate Treg activation, yielding therapeutic benefits in preclinical autoimmune models (Benne et al., 2018[13]). DEX, a potent glucocorticoid inducer of tolDCs, is effective but limited by poor solubility, rapid clearance, and systemic toxicity. However, its clinical application is hampered by poor solubility, rapid systemic clearance, and significant side effects (Madamsetty et al., 2022[45]).

To address these issues, Benne and a group of investigators (Benne et al., 2024[12]) designed a novel system where DEX was conjugated to human proteoglycan (hPG) via a lysine tetramer (K4) and biodegradable spacer, then encapsulated within DSPG liposomes (hPGK4-DEX liposomes) (Benne et al., 2024[12]). In arthritic mice, this approach reduced autoantibody levels, expanded Tregs, and boosted IL-10 production in inflamed joints, thereby inducing antigen-specific tolerance.

In OA, intra-articular (IA) corticosteroid injections provide only short-lived pain relief and may worsen cartilage degeneration with repeated administration. DEX-Lips formulations were developed to overcome these drawbacks by extending drug retention within the joint and enabling sustained release. Following IA injection, liposomes are efficiently taken up by synovial macrophages, key mediators of glucocorticoid action in inflamed joints, which promotes localized delivery and prolonged anti-inflammatory activity. DEX-Lips has shown superior intra-articular persistence, reduced joint swelling, protection against cartilage erosion, and lower levels of inflammatory cytokines compared with free DEX solution. These features reduce dosing frequency while enhancing chondroprotection, highlighting DEX-Lips as a promising long-acting and safer alternative for OA management (Kulikov et al., 2021[40]).

Recent studies highlight that synovial macrophage polarization plays a central role in OA progression. In OA, macrophages accumulate within the synovium, where they can adopt either a pro-inflammatory M1 phenotype or an anti-inflammatory M2 phenotype depending on the local microenvironment. This balance not only drives synovial inflammation but also influences pain modulation, as M1 and M2 macrophages contribute differently to pain initiation and resolution (Zhang et al., 2020[95]).

To address this, Teng and colleagues (Teng et al., 2023[74]) evaluated intra-articular dexamethasone-loaded liposomes (DEX-Lipo) for osteoarthritis (OA), showing improved local retention and reduced systemic exposure, along with macrophage repolarization toward the anti-inflammatory M2 phenotype. In OA models, DEX-Lipo effectively reduced synovial inflammation, preserved cartilage integrity, and suppressed macrophage infiltration and pro-inflammatory cytokines (IL-1β, TNF-α), demonstrating strong therapeutic potential (Teng et al., 2023[74]).

Formulations with slower drug release have shown superior joint protection by sustaining therapeutic effects longer than faster-releasing systems. Intra-articular DEX-Lips extended the treatment window compared to free DEX (around 10 vs. 6 days), but its effect was still less durable than polymer conjugates or crosslinked micelles (Quan et al., 2014[59]).

This limitation is linked to the structural fragility of liposomes, where drug leakage or vesicle destabilization may occur during circulation. In contrast, conjugated and crosslinked carriers retain the drug more securely. These findings highlight the importance of improving liposomal stability in the joint environment, where intra-articular delivery helps preserve vesicle integrity and prolong local activity.

Preclinical and translational studies further support this approach. For instance, TLC599, a DEX-Lips sodium phosphate formulation, showed extended joint residence of up to 120 days in canine models and has progressed to phase III clinical trials (Hunter et al., 2022[31]). Similarly, Lipotalon® (DEX palmitate, 4 mg/mL) remains the only approved liposomal intra-articular therapy available on the German market (Mitsou and Klein, 2025[48]). These examples demonstrate the clinical potential of DEX-Lips in the treatment of OA. However, most current formulations are relatively simple, focusing on sustained release without fully addressing challenges such as mechanical joint stress, heterogeneous intra-articular distribution, or macrophage-targeted delivery.

Liposomes are highly suitable for co-delivery systems since their bilayer structure can simultaneously encapsulate both water-soluble and lipid-soluble agents. This enables the incorporation of different therapeutic classes within a single carrier. In OA, where conventional oral NSAIDs and intra-articular corticosteroids are limited by toxicity, liposomal formulations of diclofenac and DEX have been developed. Using hyaluronan (HA-BAL) or collagen-modified (COL-BAL) bioadhesive liposomes, both drugs, individually or in combination, showed high loading efficiency (> 80 %), controlled release over 1-3 days, and maintained biological activity. In OA rat models, a single intra-articular dose reduced joint inflammation for up to 17 days, with HA-BAL outperforming COL-BAL. The dual-drug HA-BAL formulation was most effective, decreasing inflammation volume to 12.9 % of baseline.

Hyaluronic acid (HA) is a naturally occurring gel-like substance that supports cartilage and bone development, while also reducing inflammation and pain from joint injury or degeneration. Because of these properties, HA injections are widely used for OA pain management (Huang et al., 2019[29]).

Building on this, Chang et al. developed an HA-based liposomal system co-loaded with diclofenac (DIC) and DEX for localized OA therapy. The formulation included both hydrophilic (DEX sodium phosphate) and hydrophobic (DEX base) forms of DEX along with DIC, allowing fast therapeutic action and sustained release for over 7 days. In OA mouse models, the dual-drug liposomes significantly reduced inflammation and leukocyte infiltration with only minor tissue reactions (Chang et al., 2021[15]).

In vivo results demonstrated that HA-Lipo-DIC/DEX was more effective in reducing paw swelling than the individual drugs. After 28 days, paw thickness decreased to 2.74 mm with the dual-drug system, compared to 4.60 mm for DIC and 3.73 mm for DEX alone (Figure 8A(Fig. 8); Reference in Figure 8: Chang et al., 2021[15]), confirming its superior anti-inflammatory efficacy. Further evaluation using in vivo fluorescence imaging showed that, following 7 days without treatment and 14 days of therapy, the treated group displayed the lowest fluorescence intensity in the affected paw (Figure 8B(Fig. 8), C, p < 0.001). This indicates a significant reduction in neutrophil elastase activity and overall inflammation (Chang et al., 2021[15]).

However, for optimal outcomes, both drugs should ideally act on the same target cells (such as macrophages). If their targets differ, it may lead to uneven therapeutic effects. In such cases, strategies like controlled or staged drug release become important. Thus, while dual-drug liposomes are promising, their success depends on proper drug selection, controlled release design, and precise targeting of diseased tissue.

In OA, cartilage deterioration arises not only from chronic inflammation but also from impaired lubrication at the articular surface, which increases friction and accelerates mechanical wear. Recent research highlights the potential of large, empty liposomes as biomimetic lubricants when administered intra-articularly. These vesicles coat cartilage surfaces, reduce shear stress, and limit further degeneration independently of drug delivery. For instance, multilamellar liposomes have been shown to restore boundary lubrication in OA rat models, mimicking the role of natural synovial phospholipids and reducing cartilage damage.

Normal cartilage lubrication relies on hyaluronic acid, lubricin, and phospholipids, which act synergistically to maintain smooth articulation. In OA, depletion of these components disrupts joint lubrication. Liposomes, with amphiphilic bilayers, can restore function by forming hydration shells, boundary films, and filling surface irregularities.

Wechsler and colleagues (Wechsler et al., 2025[84]) developed MM-II, a liposomal formulation designed to function within OA-relevant temperature ranges. To investigate its mechanism and structural effects, cartilage coating was assessed using fluorescently labeled MM-II under compressive and non-compressive conditions. The lubricative function was quantified in cartilage-on-glass friction assays and pin-on-disc wear models, while intra-articular distribution was examined in healthy and OA rabbit knees. Structural protection was further evaluated in a rat OA model, comparing MM-II with individual DMPC or DPPC liposomes, their combination, and vehicle controls. Results demonstrated that MM-II preferentially adhered to cartilage under load, forming a stable boundary layer that reduced friction and wear. In rats, MM-II decreased tibial cartilage degeneration by 53 % and limited mononuclear cell infiltration. These findings suggest that MM-II provides chondroprotection primarily through boundary lubrication, with additional synovial modulation contributing to clinical pain relief, highlighting its potential as a biomimetic lipid-based OA therapy. Figure 9(Fig. 9) (Reference in Figure 9: Wechsler et al., 2025[84]) illustrates the study design (Figure 9A(Fig. 9)) and the proposed mechanism of action (Figure 9B(Fig. 9)) (Wechsler et al., 2025[84]).

Although drug-loaded liposomes, such as DEX formulations, emphasize anti-inflammatory effects, their contribution to lubrication remains underexplored. Optimizing liposomal size, lipid composition, and hydration properties could maximize both tribological performance and therapeutic efficacy in OA.