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An ROS/DAMP dual-scavenging nanomedicine for normalizing macrophage polarization and microbiome in colitis


Introduction

Inflammatory bowel illness (IBD) is a serious gastrointestinal illness and poses nice risk to human well being worldwide, which is characterised by the chronical irritation of gastrointestinal tissues [1]. Present IBD remedy approaches largely make use of small molecular medication or antibody medication to alleviate acute injury or stopping relapse episodes [2]. Nevertheless, extended use of those therapeutics could considerably improve the danger of great problems, together with autoimmune response, infections, and organ injury resulting from systemic unwanted side effects [3]. Furthermore, it’s well-established that IBD is a multifactorial illness with advanced pathogenesis. Intestinal irritation may end up in the discharge of damage-associated molecular patterns (DAMPs), that are recognized by the innate immune system through classical sample recognition receptors, triggering immune responses [4], [5]. DAMPs stimulation would trigger the discharge of pro-inflammatory effector molecules by epithelial cells, endothelial cells, and innate immune cells, ensuing within the activation of adaptive immune response [6]. The recruited inflammatory cells may generate reactive oxygen species (ROS), additional exacerbating the pathological inflammatory response [7]. Subsequently, it’s vital to develop new remedy methods that concentrate on each intestinal DAMPs and ROS for efficient and cooperative remedy of IBD.

Nanomaterials with immunoregulatory means have attracted intensive attentions. These nanomaterials introduced exceptional IBD therapeutic results by regulating immune responses. A lot of the present research on this space give attention to utilizing catalytic nanomaterials to eradicate ROS generated from inflammatory cells, equivalent to cerium dioxide (CeO2) and NiCo2O4 nanoparticles (NPs) [8], [9], [10], [11], [12]. Nevertheless, stories that mediate the DAMPs-dependent inflammatory responses for IBD remedy are nonetheless uncommon. It’s anticipated that nanomaterials with twin ROS/DAMPs scavenging means might afford enhanced therapeutic impact on IBD. Zeolitic imidazolate framework (ZIF), a subcategory of metal-organic frameworks, have gained broad consideration in biomedicine [13], [14]. ZIF-8, a consultant nanomaterial in ZIF household, was reported to scavenge anionic DNA resulting from electrostatic adsorption and π − π stacking [15]. Cell-free DNA (CfDNA), a typical DAMPs launched from inflammatory cells or intestine microbiome, was revealed to play an vital position in Toll-like receptors (TLR-9) mediated proinflammatory signaling pathways [16], [17].

Primarily based on the insights above, right here we embellished CeO2 NPs with ZIF-8 coating, forming ZIF-8 coated CeO2 (ZCC) NPs with a core-shell construction as a drug-free therapeutic possibility for clinically adaptable ulcerative colitis (UC, one sort of IBD) remedy (Fig. 1). The ZCC NPs could possibly be simply formulated into orally administrable formulation by complexing with Eudragit S100 (ES100) or rectal enema formulation by integrating with sodium alginate hydrogel (SA gel), thus enhancing their translational potential in a medical context. The ZCC NPs possess appreciable anti-inflammatory impact proudly owning to their ROS and DAMPs scavenging means, which have been able to activating the M2 polarization of pro-inflammatory macrophages, leading to elevated anti-inflammatory cytokines and diminished pro-inflammatory cytokines. Because of the ameliorated intestinal irritation, the ZCC NPs additionally normalized the intestine microbiota and restored intestinal mucosal construction and capabilities. In vivo analysis revealed that ZCC NPs confirmed evidently superior therapeutic impact than 5-ASA, a extensively used drug for IBD remedy in medical apply. Our research revealed that ZCC NPs can considerably reshape the pro-inflammatory immune composition in UC-affected gut through twin ROS/DAMPs scavenging, providing a drug-free method for UC remedy within the clinics.

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