Surface-engineered hyaluronic acid-coated lyotropic liquid crystalline nanoparticles for CD44-targeting of 3-Acetyl-11-keto-β-boswellic acid in rheumatoid arthritis treatment

Abstract

Background

In the current era of the global increase in autoimmune and inflammatory disorders, predominantly rheumatoid arthritis (RA), there is mounting interest in developing advanced, safe, and patient-compliant treatment strategies. Phytoconstituents have gained more attention in recent years as budding complementary medicines for RA. Among them, 3-Acetyl-11-keto-β-boswellic acid (AKBA), derived from Boswellia serrata extract, is considered a promising phytoconstituent due to its anti-inflammatory and anti-arthritic potential. However, due to its poor solubility, low bioavailability (less than 10%), and poor permeability, its therapeutic potential is limited. Therefore, to overcome these issues, we have developed novel hyaluronic acid-surface-engineered lyotropic liquid crystalline nanoparticles encapsulating AKBA (HA-AKBA-LCNP) for cutaneous site-specific distribution and enhanced therapeutic effectiveness in RA.

Results

The quality-by-design-based optimized uncoated LCNP (N-AKBA-LCNP) and HA-AKBA-LCNP exhibited particle sizes below 150 nm and entrapment efficiency (%) close to 80%, making them suitable for cutaneous penetration and availability at the disease site. The cell viability studies in the RAW264.7 cell line revealed no cytotoxicity. Uncoated LCNP and HA-coated LCNP showed 1.37- and 2.19-fold improved cell uptake, respectively, compared to free form. An in vitro study also demonstrated a significant anti-inflammatory effect of the developed LCNP system against RAW264.7 cells, characterized by a decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines. The N-AKBA-LCNP and HA-AKBA-LCNP embedded gels demonstrated improved permeation (2.34- and 2.40-fold, respectively) and improved retention (4.98- and 6.73-fold, respectively) of AKBA in the viable dermal layers compared to the free AKBA gel. In vivo investigation revealed a significant depletion in paw edema (p < 0.0001), inflammatory cytokine levels (p < 0.0001), and CD44 expression (p < 0.001) by HA-AKBA-LCNP in the Freund’s Complete Adjuvant-induced rat model of arthritis.

Conclusion

The study results exhibited the promising potential of HA-functionalized AKBA-loaded LCNP as a targeted, biocompatible, and efficient dermal delivery approach for an enhanced treatment strategy to counter the RA disease burden.

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Materials

AKBA (> 94% purity) was purchased from Gurjar Phytochem Pvt. Ltd. (Madhya Pradesh, India). HA (Molecular weight ≈ 10,000 Da) was obtained from Meteoric Biopharmaceuticals Pvt. Ltd. LPS (rough strains) from Escherichia coli (Rd mutant), 4’, 6-diamidine-2’-phenylindole dihydrochloride (DAPI), 2’, 7’-dichlorofluorescein (DCF), and FCA were purchased from Sigma Aldrich. Stearyl amine and Coumarin-6 were procured from Tokyo Chemical Industry Co., Ltd. Deuterated dimethyl sulphoxide (d-DMSO) and deuterated water (D20) were bought from SRL Pvt. Ltd, (Mumbai, India). Hydrogen peroxide solution 30% was purchased from Rankem chemicals. Dulbecco’s Modified Eagle Medium (DMEM) with high glucose was obtained from Gibco (New York, USA). Fetal bovine serum (FBS), RDP-Trio reagent, mannitol, Phosphate-Buffer Saline (PBS) pH 7.4, dialysis membrane, chloroform, diethyl pyrocarbonate-treated water, and isopropanol were acquired from Himedia (Mumbai, India). 3-(4,5-Dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide (MTT) was procured from Invitrogen (Thermo Fisher Scientific). iScript cDNA synthesis kit and iTaq™ Universal SYBR® Green Supermix were acquired from BIO-RAD. Tumor necrosis factor-alpha (TNF-α), Interleukin (IL)−10, and CD44 Primers are procured from Integrated DNA Technologies. Milli-Q water (ultrapure deionized water) was collected from an in-house Milli-Q water purification system, Millipore (USA).

Priya, S., Verma, V., Roy, A. et al. Surface-engineered hyaluronic acid-coated lyotropic liquid crystalline nanoparticles for CD44-targeting of 3-Acetyl-11-keto-β-boswellic acid in rheumatoid arthritis treatment. J Nanobiotechnol 23, 725 (2025). https://doi.org/10.1186/s12951-025-03846-5