Perioperative Collagen IV-Targeted Ac2-26 Nanoparticles Enhance Anastomotic Healing in Acute Crohn's Disease-Like...

This preclinical study investigates a novel targeted collagen type IV nanoparticle formulation, Ac2-26 coated with chitosan and pectin ((pc)-Col-IV-Ac2-26-NPs), to promote anastomotic healing in a model of acute Crohn's disease (CD) with distal colo-colonic anastomosis, using intraperitoneal, oral and rectal delivery to optimize therapeutic effects while minimizing systemic immunosuppression.

Surgery remains critical for CD-patients due to irreversible tissue damage, with anti-inflammatory therapies increasing the risk of postoperative complications like anastomotic leaks.

Female BALB/c mice (n=152) with CD-like colitis (2,4,6-Trinitrobenzenesulfonic acid) were randomized to receive (pc)-Col-IV-Ac2-26-NPs or scrambled NPs intraperitoneally, orally, or rectally every 3.5 days pre- and postoperatively, followed by distal end-to-end colo-colonic anastomosis. Perioperative outcomes (weight loss, disease activity index (DAI)), anastomotic healing scores (endoscopic, histologic), and immunohistochemical (IHC) markers were assessed on postoperative days (POD) 3 and 7.

NPs accumulated selectively at the anastomosis in a route-dependent manner and associated with higher collagen expression (P<0.0001), reduced pro-inflammatory (nuclear RelA; iNOS+-M1 macrophages, all P<0.0001) and increased pro-resolving markers (ANXA1; Arg-1+-M2 Macrophages, all P<0.0001) at the anastomotic site. These effects were most pronounced with rectal delivery, corresponding with improved preoperative DAI (P=0.03) and both endoscopic (POD3:P<0.0103; POD7:P<0.0077) and histologic (POD3:P<0.0112; POD7:P<0.0170) healing scores. While intraperitoneal delivery produced similar outcomes, oral delivery showed the weakest effect.

(pc)-Col-IV-Ac2-26-NPs promote anastomotic healing during CD-colitis through targeted, route-dependent immunomodulation and tissue repair, with rectal delivery showing the highest local efficacy. These findings support their potential as locally acting, non-immunosuppressive therapy for high-risk CD-patients undergoing intestinal surgery.