Dietary Lactobacillus rhamnosus GG extracellular vesicles (LGG-EV) synergistically enhanced anti-PD-1 immunotherapy efficacy against colorectal cancer. It was associated with improved tumor immunosuppressive environment, the abundance of beneficial bacteria and elevated specific serum metabolites.

Rationale: Inflammatory bowel diseases (IBDs) are still awaiting innovative treatments that can maximize the efficiency of site-specific drug release in the colon while enhancing intestinal homeostasis. Methods: Herein, we present multilayer-coated mesoporous silica (MSs) which release payload drugs specifically in the colon tract in the presence of azoreductase produced by the gut microbiota, and simultaneously rejuvenate the tryptophan metabolism of the microbiome to induce activation of the aryl hydrocarbon receptor (AHR) for increased anti-inflammatory effects. The MSs were prepared by using cucurbit[8]uril (CB[8]) as a supramolecular “handcuff” to assemble chitosan/hyaluronic acid multilayers on the periphery of a mesoporous silica core. Results: Strikingly, although MSs remained fairly stable in both acidic and neutral pH, they exhibited excellent responsiveness towards dithionite, an azo-reducing agent employed as a substitute to mimic the specific azoreductase environment in vitro. In comparison with the drug in its free form, hydrocortisone-loaded MSs showed optimized accumulation of therapeutics in the colonic mucosa with minimized premature release in the upper gastrointestinal tract in in vivo imaging and biodistribution studies. The enhanced therapeutic effects of MSs were confirmed in dextran sodium sulfate-induced colitis in mice with promoted colonic epithelial barrier integrity, elevated level of AHR agonists and modulated production of inflammatory cytokines. Furthermore, 16S rRNA analysis showed that the disrupted gut homeostasis of colitic mice was partly corrected by MSs. Conclusion: This novel drug delivery system using self-assembly of tryptophan-functionalized chitosan, which was precomplexed with CB[8], and azobenzene-functionalized hyaluronic acid on the surface of mesoporous silica nanoparticles provides a synergistic gut microbiota-targeting approach for IBD therapy.

Honokiol, a biologically active compound isolated from Magnolia bark, has been shown to possess promising anticancer effect through induction of apoptosis. However, there is a relative lack of information regarding its anti‑metastatic activity. Renal cell carcinoma (RCC) is the most common malignancy of the adult kidney and is known for high risk of metastasis. Clinically, therapeutic methods for metastatic RCC cases are limited and efforts to exploit new treatments are still ongoing. The results of our current investigation first revealed that honokiol suppressed the proliferation of different human RCCs without affecting cell viability. In addition, honokiol inhibited migration of highly metastatic RCC 786‑0 cells and stimulated the activity of small GTPase, RhoA. Furthermore, phosphorylated myosin light chain (MLC) and excessive formation of actin stress fibers were identified in 786‑0 cells treated with honokiol. Interestingly, the pharmacological Rho‑associated protein kinase (ROCK) inhibitor Y‑27632 attenuated contraction of actin stress fibers induced by honokiol and abrogated honokiol‑mediated inhibition of cell migration. Together these important findings suggest that honokiol suppresses the migration of highly metastatic RCC through activation of RhoA/ROCK/MLC signaling and warrants attention in the treatment of RCC metastasis as a novel therapeutic approach.