An oral berberine nanocapsule platform orchestrates microbiota for potent gastric cancer chemotherapy.

Systemic chemotherapy for gastric cancer is frequently compromised by debilitating, dose-dependent toxicities, necessitating innovative adjunctive strategies that balance therapeutic efficacy with systemic safety. While natural products represent a promising source of candidates, their clinical translation is frequently hindered by intrinsic pharmacokinetic barriers. To address this, we developed the oral resident binary intestinal therapy (ORBIT) system, an excipient-free nanocapsule platform engineered for prolonged gut residency. Unlike conventional pharmaceutical formulations that depend on synthetic excipients, ORBIT is an excipient-free, self-assembled nanocapsule composed of a high-density dopamine-functionalized hyaluronic acid (hDAHA) shell encapsulating a berberine (BBR) core. This unique architecture provides a protective shield for BBR against premature degradation while utilizing the adhesive properties of the hDAHA shell to enhance gastrointestinal retention. ORBIT enables sustained, pH-responsive drug release, providing robust in situ shielding of the intestinal mucosa against oxaliplatin-induced injury and preserving epithelial barrier integrity. In preclinical gastric cancer models, the ORBIT regimen synergistically potentiates oxaliplatin-mediated tumor suppression while dramatically ameliorating systemic toxicity. Mechanistically, ORBIT administration profoundly remodels the microbiome-immune axis, specifically enriching beneficial commensals such as Akkermansia to drive increased intratumoral infiltration of CD8⁺ T cells. This study establishes a new oral nanotherapeutic paradigm for chemo-immunotherapy, presenting a compelling and clinically translatable strategy to optimize gastric cancer treatment outcomes.