Autotaxin-Scavenging Nanoliposomes for Prolonged Colon Retention and Autophagy-Mediated Mucosal Immune Restoration in Colitis.

Inflammatory bowel disease (IBD) is an immune-mediated disorder driven by overactivation of autotaxin (ATX), which elevates lysophosphatidic acid (LPA) signaling and suppresses autophagy, exacerbating intestinal inflammation. Given the pivotal role of autophagy in maintaining intestinal homeostasis, inhibiting ATX offers a dual therapeutic mechanism by both restoring autophagic activity and attenuating LPA-mediated inflammatory responses. Current treatments are hindered by nonspecific immunosuppression and frequent systemic side effects, underscoring the need for targeted, multifunctional therapeutic strategies. Here, we present a dual-functional nanotherapeutic platform, ATX-scavenging liposomes loaded with rapamycin (AS-Lipo@R), engineered for the oral treatment of acute colitis. Our proposed formulation incorporates BMP-22, a lipid ATX inhibitor that simultaneously functions as a structural building block of the liposomal membrane. Rapamycin, an autophagy activator, is encapsulated within the bilayer of liposomes. We confirmed that AS-Lipo@R exhibits strong binding affinity to extracellular ATX and mediates its lysosomal degradation upon cellular internalization, thereby demonstrating its ATX-scavenging property. In vitro, AS-Lipo@R inhibited inflammatory macrophage activation, promoted M2 macrophage polarization, and substantially restored autophagic activity in LPS/IFN-γ-stimulated macrophages. In vivo, oral administration of AS-Lipo@R led to preferential accumulation in ATX-overexpressing inflamed colonic tissue, resulting in reduced pro-inflammatory cytokine production, recovered autophagy, and enhanced intestinal barrier integrity in colitis mice. These findings highlight AS-Lipo@R as a synergistic and targeted nanomedicine that simultaneously modulates ATX and autophagy pathways, offering novel insights into immunomodulatory strategies for IBD treatment.