Oral Supramolecular Adsorbent for Preventing Chemo‐Induced Gastrointestinal Mucositis and Microbial Dysbiosis and for Enhancing Chemoimmunotherapy

The addition of immune checkpoint blockade (ICB) to cytotoxic chemotherapy has emerged as the first‐line treatment for multiple cancers. Paradoxically, cytotoxic chemotherapy may limit the therapeutic potential of ICB by significantly impairing the largest immune organ, the gastrointestinal (GI) tract, and driving gut microbial dysbiosis. Here, an orally administered polymeric adsorbent containing a supramolecular motif (named SPORA‐SN9) is reported, which can selectively remove chemotherapeutics from the GI tract, thereby preventing chemotherapy‐induced GI mucositis and microbial dysbiosis and providing better chemoimmunotherapy synergy. By theoretical design and experimental screening of the molecular recognition motifs, SPORA‐SN9 exhibits superior complexation capacity for doxorubicin and irinotecan and high selectivity over a range of commonly used combinational medications. In mouse models of chemotherapy‐induced GI mucositis, SPORA‐SN9 protects the integrity of the GI tissues and the homeostasis of the gut microbiota. Finally, the addition of SPORA‐SN9 enhances the efficacy of chemoimmunotherapy in tumor‐bearing mice. SPORA‐SN9 offers a translational approach for supramolecular chemistry to modulate complex biosystems by selectively removing target substrates from the GI tract. An orally administered polymeric adsorbent (SPORA‐SN9) that can selectively adsorb chemo exposure in the GI tract is developed. The SPORA‐SN9 sharply decreases the toxic chemo content of the gastrointestinal (GI) lumen, thereby preventing chemo‐induced GI mucositis and chemo‐induced microbial dysbiosis. Interestingly, the protected gut microbiome improves the antitumor efficacy of the followed immune checkpoint blockade therapy.