Antimicrobial-potentiated colorectal cancer therapy with synchronized tumoricidal immunity via a self-deliverable nanopeptide.

Abstract

As one of the core pathogens of colorectal cancer (CRC), fusobacterium nucleatum (Fn) contributes to tumor progression, drug-resistance, and immunosuppressive microenvironment, resulting in low therapeutic outcomes. Developing multifunctional nanodrugs capable of tandem killing cancer cells and intratumoral Fn while circumventing drug-resistance and remodeling immunosuppressive niche is very promising but faces enormous challenges. Herein, a self-deliverable nanodrug composed of single-component peptide was developed to combat Fn-colonized CRC. Relying on peptide self-assembly, the nanodrug was readily fabricated without carriers, which dually killed CRC cells and Fn via membrane disruption mechanism and thus mitigated the drug-resistance. To selectively eliminate cancer cells and pathogens, an acidity-activated charge conversion strategy was exploited to decorate peptide drug. Concurrently, this approach mitigated hemolytic side effects and enhanced pharmacological stability. Notably, peptide-mediated immunogenic cell death (ICD) and killed Fn further separately released damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) to synergistically activate the host immune response for immunotherapy. Furthermore, the multifunctional nanopeptide could block epithelial-mesenchymal transition (EMT) process, showing the potential of inhibiting Fn-colonized CRC metastasis. Collectively, this single-component peptide nanodrug demonstrates a well-defined composition, facile synthesis, tumor-specific activation, and superior therapeutic efficacy in CRC treatment, presenting a strong case for its future clinical application. STATEMENT OF SIGNIFICANCE: Intratumoral Fusobacterium nucleatum (Fn) drives colorectal cancer (CRC) progression, chemoresistance, and immunosuppression, creating a critical barrier to effective therapy. To address this, we developed a single-component, self-deliverable nanopeptide with an acidity-activated charge-conversion mechanism. This nanodrug achieved tandem membrane-disruption-mediated killing of both CRC cells and intratumoral Fn, a physical mechanism that circumvents conventional drug resistance. Its acidity-activated charge conversion further ensured tumor-selective activation while minimizing hemolytic toxicity. Beyond its dual cytotoxic action, it also activated host antitumor immunity and blocked epithelial-mesenchymal transition (EMT) in Fn-infected CRC. With its well-defined composition, facile synthesis, and tumor-specific activation, this peptide-based nanoplatform offers a transformative strategy for overcoming pathogen-driven therapeutic resistance and advancing CRC treatment toward clinical translation.