Pathogen‐Guided In Situ Secondary H‐Aggregate Assembly for Self‐Amplified Theranostic of Fusobacterium nucleatum ‐Infected Colorectal Cancer

ABSTRACT Targeting intratumoral pathogens holds great potential for cancer theranostics, yet achieving tumor‐specific action remains a formidable challenge. Fusobacterium nucleatum ( Fn ) acts as a crucial pathogenic factor driving colorectal cancer (CRC) progression and therapeutic response. Herein, we propose an innovative “confine‐release‐target‐reassemble (CRTR)” strategy for the in situ pathogen‐guided secondary self‐assembly of H‐aggregates within Fn ‐infected CRC. A boron‐dipyrromethene (BODIPY)‐derived photothermal agent, BDP‐GalNAc, is rationally designed to specifically recognize Fn through high‐affinity interaction between GalNAc and Fn ‐expressed Fap2 lectin. Loading BDP‐GalNAc into glutathione (GSH)‐responsive degradable zwitterionic nanogels constructs theranostic nanoplatform BDP‐GalNAc NGs. The confined microenvironment supports the formation of H‐type sub‐aggregates thereby inhibiting uncontrolled self‐assembly. Upon GSH‐triggered nanogel disintegration, the encapsulated sub‐aggregates liberate and subsequently undergo Fn ‐guided secondary self‐assembly into H‐type super‐aggregates anchored on bacterial surface, driven by multiple intermolecular interactions. Such hierarchical assembly behavior remarkably improves intratumoral enrichment and retention efficiency, amplifies photoacoustic imaging signals, and exerts potent photothermal effect that simultaneously eradicates intratumoral Fn and induce robust gasdermin D‑mediated pyroptosis of CRC cells. Pyroptosis‐associated immunogenic cell death further initiates a strong systemic anti‐tumor immune response, ultimately realizing synergistic photothermal‐immunotherapy. This elaborately designed CRTR paradigm circumvents inherent drawbacks of conventional nanotherapeutics and opens a promising avenue for precise theranostics of microbiota‐associated malignancies.