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.