Modulation of Intratumoral Fusobacterium nucleatum to Enhance Sonodynamic Therapy for Colorectal Cancer with Reduced Phototoxic Skin Injury

Abstract

Intratumoral pathogens can contribute to cancer progression and affect therapeutic response. Fusobacterium nucleatum, a core pathogen of colorectal cancer (CRC), is an important cause of low therapeutic efficacy and metastasis. Thus, the modulation of intratumoral pathogens may provide a target for cancer therapy and metastasis inhibition. Herein, we propose an intratumoral F. nucleatum-modulating strategy for enhancing the therapeutic efficacy of CRC and inhibiting lung metastasis by designing an antibacterial nanoplatform (Au@BSA-CuPpIX), which produced reactive oxygen species (ROS) under ultrasound and exhibited strong antibacterial activity. Importantly, Au@BSA-CuPpIX reduced the levels of apoptosis-inhibiting proteins by inhibiting intratumoral F. nucleatum, thereby enhancing ROS-induced apoptosis. In vivo results demonstrated that Au@BSA-CuPpIX effectively eliminated F. nucleatum to enhance the therapeutic efficacy of sonodynamic therapy (SDT) for orthotopic CRC and inhibit lung metastasis. Notably, entrapped gold nanoparticles reduced the phototoxicity of metalloporphyrin accumulated in the skin during tumor treatment, preventing severe inflammation and damage to the skin. Therefore, this study proposes a strategy for the elimination of F. nucleatum in CRC to enhance the therapeutic effect of SDT, thus providing a promising paradigm for improving cancer treatment with fewer toxic side effects and promoting the clinical translational potential of SDT.

Emerging strategies for combating Fusobacterium nucleatum in colorectal cancer treatment: Systematic review, improvements and future challenges

“…Upon detecting the formation of CRC, the ideal therapeutic system should be designed. [ 251,252 ] First, the drug system must identify the receptor on the CRC cells and precisely target the cancer cells to prevent tumor spread. When the drug arrives at the CRC site, it is expected to precisely target a significant amount of pathogenic F. nucleatum in the intestinal environment and inhibit its growth.…”

Drug delivery systems for enhanced tumour treatment by eliminating intra-tumoral bacteria

“…Similarly, Huanlong Qin and co-authors designed an ultrasonic triggered albumin-based nanoplatform (Au@BAS–CuPplX), which consisted of Au nanoparticles and an antibacterial metalloporphyrin (CuPplX) sonosensitizer, to modulate intra-tumoral F. nucleatum for reinforcing the efficacy of CRC treatment and inhibiting lung metastasis. 85 Under ultrasound irradiation, Au@BAS–CuPplX displayed excellent ultrasonic-triggered ROS generation and antibacterial activity against F. nucleatum . In addition, the elimination of F. nucleatum further improved the therapeutic effect of sonodynamic therapy and suppressed the CRC metastasis.…”

Recent progress in nanomaterials for bacteria-related tumor therapy

“…Qu et al 78 developed a gold nanoparticle-based antibacterial nanoplatform by using bovine serum albumin (BSA) as a carrier to improve biocompatibility and stability (Au@BSA-CuPpIX) (Fig. 9a).…”