Oral TNF-αsiRNA delivery via milk-derived exosomes for effective treatment of inflammatory bowel disease

Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon,making it an ideal approach for treating patients with inflammatory bowel disease.However,multiple physical barriers impede the delivery of oral RNA drugs through the gastrointestinal tract.Herein,we developed a novel oral siRNA delivery system that protects nucleic acids in extreme environments by employing exosomes derived from milk to encapsulate tumor necrosis factor-alpha(TNF-α)siRNA completely.The remarkable structural stability of milk-derived exosomes(M-Exos),as opposed to those from HEK293T cells,makes them exceptional siRNA carriers.Results demonstrate that milk exosomes loaded with TNF-αsiRNA(M-Exo/siR)can effectively inhibit the expression of TNF-α-related inflammatory cytokines.Moreover,given that milk exosomes are composed of unique lipids with high bioavailability,orally administered M-Exo/siR effectively reach colonic tissues,leading to decreased TNF-αexpression and successful alleviation of colitis symptoms in a dextran sulfate sodium-induced inflammatory bowel disease murine model.Hence,milk-derived exosomes carrying TNF-αsiRNA can be effectively employed to treat inflammatory bowel disease.Indeed,using exosomes naturally derived from milk may shift the current paradigm of oral gene delivery,including siRNA.

Exosome-guided direct reprogramming of tumor-associated macrophages from protumorigenic to antitumorigenic to fight cancer

Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance.In particular,tumor-associated macrophages(TAMs),as the predominant infiltrated immune cells in a tumor,play a pivotal role in regulating the immunosuppressive tumor microenvironment.As a potential therapeutic strategy to counteract TAMs,here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages.Exosomes derived from M1-type macrophages(M1-Exo)promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency.Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability,potentiating antitumor immunity surrounding the tumor.Strikingly,these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II,offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.