The susceptibility of colorectal cancer (CRC) cells to Fusobacterium nucleatum (F. nucleatum) infection pose significant challenges to CRC treatment and prevention. This study addresses these challenges by mobilizing cGAS/STING axis activation and F. nucleatum-specific targeting, thereby achieving a multimodal treatment strategy for reversing the immunosuppressive microenvironment (ITM) and achieving targeted anti-F. nucleatum therapy. Specifically, a hybrid nanoplatform CuPpIX@HM was engineered using Escherichia coli and tumor cell membranes encapsulating ultrasound (US) stimulation-responsive copper protoporphyrin IX (CuPpIX). This design enables the precise accumulation of the nanoplatform at tumor sites following oral administration. Notably, upon US activation, CuPpIX generates a high level of reactive oxygen species (ROS), selectively eradicating F. nucleatum and exerting potent antitumor effects. Meanwhile, bacterial membrane components activate the cGAS/STING signaling pathway, effectively reversing the ITM, enhancing systemic antitumor immunity. Importantly, CuPpIX@HM exerts minimal disruption to healthy intestinal microbiota and remarkably increases the level of probiotics. In both orthotopic and liver metastasis, CRC models demonstrated that this strategy could significantly inhibit tumor growth and metastasis. Collectively, our study presents a highly targeted multimodal nanotherapy that holds strong potential to improve CRC treatment outcomes through the precision modulation of F. nucleatum and immune activation.
Introduction Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis, and Fusobacterium nucleatum (Fn) colonization further aggravates tumor progression, immunosuppression and therapeutic resistance. Conventional monotherapies are limited by insufficient tumor targeting, rapid drug clearance and failure to reverse immune suppression. Here, we fabricated cRGD-modified nanoparticles (Ag@GQDs/QUE-siP-c-L) for co-delivery of AgNPs, quercetin (QUE) and PD-L1 siRNA (siP).Methods The morphology, particle size, surface metal elements, drug content and QUE entrapment efficiency of Ag@GQDs/QUE-siP-c-L were obtained using particle size analysis, SEM, inductively coupled plasma-optical emission spectrometry (ICP-OES) and HPLC. We further detected cellular uptake, in vitro drug release, cytotoxicity, intracellular reactive oxygen species level, PD-L1 gene silencing efficiency and in vitro anti-Fn activity. Pharmacokinetics and tissue distribution of Ag and QUE were analyzed by ICP-OES and LC-MS/MS, and in vivo antitumor efficacy and biosafety were tested in Fn-colonized orthotopic 4T1 tumor mice.Results Ag@GQDs/QUE-siP-c-L exhibited uniform spherical morphology (195.87± 15.96 nm) with high encapsulation of QUE. cRGD modification enhanced Ag/QUE cellular uptake in 4T1 cells, with pH-responsive release accelerated under tumor acidic conditions. The nanoparticles exhibited selective tumor cytotoxicity, induced oxidative stress, downregulated PD-L1 mRNA, and exerted potent anti-Fn activity in vitro. Pharmacokinetics revealed increased AUC0-t and reduced clearance compared with free drugs, and cRGD modification promoted tumor accumulation and retention of drugs. In vivo preliminary experiments proved the Ag@GQDs/QUE-siP-c-L formulation suppressed tumor growth with a tumor inhibition rate of 45%, and effectively modulated the tumor immune microenvironment: it increased tumor-infiltrating CD3⁺CD4⁺ T cells, reduced PD-L1⁺CD11c⁺ dendritic cells, and decreased the proportions of immunosuppressive Tregs and MDSCs. Hematoxylin-eosin staining and serum liver-kidney biochemistry confirmed no obvious systemic toxicity.Conclusion Ag@GQDs/QUE-siP-c-L serves as a multimodal nanoplatform for Fn-associated TNBC with combined in vitro antibacterial, gene silencing and in vivo antitumor immunomodulatory effects, showing great potential for future translational research.
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