Youshuai Meng,1,* Chuan Chen,1,2,* Ronggui Lin,1,3,* Linlin Zheng,4 Yanying Fan,5 Mengdi Zhang,1 Ziqi Zhang,1 Han Shi,1,3 Xiaohan Zheng,1,3 Junyu Chen,1 Dezhao Chen,1,3 Tianhong Teng,1,3 Bing Chen1 

1Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China; 2Innovation Center for Enzyme Catalysis and Drug Synthesis, School of Pharmacy, Xiamen Medical College, Xiamen, 361023, People’s Republic of China; 3Department of General Surgery/ Department of Obstetrics & Gynecology, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China; 4Department of Oncology, Affiliated Hospital of Putian University, Putian, 351199, People’s Republic of China; 5Fuzhou Children’s Hospital of Fujian Province, Fuzhou, 350005, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Bing Chen, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China, Email BingChen_001@126.com, BingChen_001@fjmu.edu.cn Tianhong Teng, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, 350122, People’s Republic of China, Email tianhongteng24@fjmu.edu.cn

Background: The dense and fibrotic nature of the pancreatic tumor microenvironment significantly contributes to tumor invasion and metastasis. This challenging environment acts as a formidable barrier, hindering effective drug penetration and delivery, which ultimately limits the efficacy of conventional cancer treatments. Gold nanoparticles (AuNPs) have emerged as promising nanocarriers to overcome the extracellular matrix barrier; however, their limited targeting precision, poor delivery efficiency, and insufficient photothermal conversion present challenges.
Methods: We developed triphenyl phosphonium-functionalized high-branch gold nanoparticles, denoted as Dox@TPAu, to enhance drug delivery and targeting capabilities. The targeted penetration, biopharmaceutical and pharmacokinetic properties of Dox@TPAu were characterized, and the synergistic therapeutic effect was evaluated by the BxPC-3 xenograft tumor mouse model.
Results: Dox@TPAu exhibits superior photothermal conversion efficiency (91.0%) alongside a high drug loading efficiency (26%) and effective photo-triggered drug-release potential. This Dox@TPAu drug delivery system adeptly accumulates at tumor sites due to its unique properties, enabling targeted localization within cancer cells and the mitochondria of stromal fibroblasts. This localization disrupts mitochondrial function and transfer—processes crucial for energy production, metabolism, and cell signaling within the tumor microenvironment. Pharmacokinetic analyses revealed an optimal spatiotemporal distribution of Dox@TPAu at the tumor site. This strategic accumulation enables precise disruption of both the physical barrier and cancer cells, enhancing treatment efficacy through near-infrared light-triggered local chemo-photothermal synergistic therapy.
Conclusion: Our findings demonstrate that this innovative strategy effectively leverages the unique properties of mitochondria-targeting, virus-like AuNPs for precise and efficient stromal depletion, presenting a promising approach to enhance the efficacy of pancreatic cancer treatment.

Keywords: mitochondria-targeting, gold nanoparticle, stromal depletion, chemo-photothermal therapy, pancreatic cancer