CD44-targeted immunoliposomes for IL-1β knockdown modulate macrophage-mediated inflammation

Chronic inflammation is the underlying cause of the pathogenesis of many critical diseases. Therapeutic interventions for controlling inflammation via targeted gene knockdown of inflammatory mediators have emerged as a promising approach for regulating uncontrolled inflammation. This study explores the potential of siIL-1β-anti-CD44-Liposomes (SIL) as a potent anti-inflammatory therapy via gene-specific knockdown of IL-1β mRNA through CD44-targeted Immunoliposomes. The designed SIL exhibited a uniform size of 131.1 ± 0.5 nm with a quasi-spherical morphology and sustained release of siIL-1β within 24 hours. The efficacy of SIL in rendering anti-inflammatory effects was validated on cellular as well as preclinical models of inflammation. SIL treatment resulted in a significant reduction of IL-1β and TNF-α at both gene and protein expression levels, alongside down-regulation of additional pro-inflammatory markers, coupled with an increase in the anti-inflammatory cytokine IL-4. Furthermore, SIL modulated macrophage-T cell crosstalk, attenuating cytokine-driven T cell effector responses. In the preclinical model of inflammation, SIL demonstrated robust anti-inflammatory activity reflected by decreased systemic inflammatory markers such as C-reactive protein, and by broad immunomodulatory effects at the tissue and cytokine levels. Collectively, these findings underscore the therapeutic potential of siIL-1β-anti-CD44-liposomes as a targeted and multifaceted intervention for chronic inflammatory disorders. Delivery of IL-1β siRNA via CD44-targeted Immunoliposomes exhibits prolonged immunomodulatory effects, by suppressing NLRP3, reducing pro-inflammatory cytokine production, and attenuating systemic inflammation at both tissue and cytokine levels.