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Abstract <p>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 <i>Akkermansia</i> 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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月27日

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  • Shuai Gong,
  • Yuxiang Zhang,
  • Wei Du,
  • Chong Zhang,
  • Nai Wu,
  • Xiuzhong Zhang,
  • Zeqiang Ren,
  • Yi Zhang,
  • Pengbo Zhang,
  • Chenyue Zhan,
  • Xiaoyu Wu

摘要

Abstract

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.

Graphical Abstract