It is proven that β-amyloid (Aβ) aggregates containing cross-β-sheet structures led to oxidative stress, neuroinflammation, and neuronal loss via multiple pathways. Therefore, reduction of Aβ neurotoxicity via inhibiting aggregation of Aβ or dissociating toxic Aβ aggregates into nontoxic forms might be effective therapeutic methods for Alzheimer’s disease (AD) treatment. This study was designed to explore interference of chitosan oligosaccharides (COS) on β-(1-42)-amyloid protein (Aβ42) aggregation and Aβ42-induced cytotoxicity. Here it was demonstrated that COS showed good blood-brain barrier (BBB) penetration ability in vitro and in vivo. The experimental results showed that COS efficiently interfered with Aβ42 aggregation in dose- and degree of polymerization (DP)-dependent manners, and COS monomer with DP6 showed the best effect on preventing conformational transition into β-sheet-rich structures. Based on the binding affinity analysis by microscale thermophoresis (MST), it was confirmed that COS could directly bind with Aβ42 in a DP-dependent manner. Our findings demonstrated that different performance of COS monomers with different DPs against Aβ42 assembly was, to some extent, attributable to their different binding capacities with Aβ42. As a result, COS significantly ameliorated Aβ42-induced cytotoxicity. Taken together, our studies would point towards a potential role of COS in treatment of AD.

Intestinal localized inflammations are recognized as key contributors to the incidence and progression of diverse extraintestinal disorders. Probiotic colonization has been increasingly highlighted for its potential to modulate susceptibility and progression of such diseases. Considering the adhesion‐ and colonization‐related challenges posed by multiple physiological and pathological characteristics in the intestine, a microenvironment self‐adaptive nanoarmor is developed. Partially acetylated chitosan oligosaccharides (CS) were employed to tune the adaptability and responsiveness of nanoarmor, enabling efficient interaction with the intestinal interface under dynamic conditions. Notably, Chitinase‐3‐like protein 1 (CHI3L1), an inflammation‐related secreted glycoprotein, served as a colonized niche to facilitate probiotics colonization in pathological microenvironments by leveraging the specific interaction between chitin‐like fragment and CHI3L1. By combining the intestinal microenvironment self‐adaptive nanoarmor with the inherent anti‐inflammatory properties of Lactobacillus plantarum ST‐III ( L. plantarum ), the nanocoated bacteria demonstrated significantly improved performance in alleviating intestinal mucosal inflammation, restoring gut barrier integrity, and reestablishing microbial homeostasis. Furthermore, the nanocoated bacteria showed significant therapeutic potential in treating Parkinson's disease (PD), a model for extraintestinal disorders, as evidenced by their ability to improve motor behavior disorders, reduce dopaminergic neuronal death, and mitigate neuroimmune responses. This approach proposes new insights into the living therapeutics for the treatment of extraintestinal diseases.

Microbial infections often disrupt the delicate balance of host commensal microbiota, leading to dysbiosis and recurrent infections, yet current therapies lack the capacity to simultaneously eradicate pathogens and restore ecological homeostasis. Here, we report a synergistic therapeutic strategy for Candida vaginitis that integrates targeted pathogen clearance with vaginal microecosystem restoration. We engineer a vaginal microenvironment‐degradable hydrogel, HCS/FUC@Lab ^PC , which self‐assembles from highly deacetylated high molecular‐weight chitosan oligosaccharide (HCS) and fucoidan (FUC) to encapsulate Lactobacillus (Lab) coated with procyanidine (PC). Within the vaginal microenvironment, the hydrogel gradually degrades and releases HCS, which efficiently eliminates Candida albicans ( C. albicans ) by disrupting cell wall integrity and interfering MAPK related signaling. FUC and PC further contribute to microenvironmental remodeling through their intrinsic anti‐inflammatory and antioxidant activities. This remodeling facilitates stable colonization of Lab, which subsequently reinforces barrier integrity through competitive exclusion and metabolic modulation. In murine models, this approach effectively disrupts the infection–dysbiosis–recurrence vicious cycle, supporting an integrated therapeutic strategy that combines pathogen clearance, microenvironmental remodeling, and microecosystem restoration.