A multistage drug delivery approach for colorectal primary tumors and lymph node metastases

Yihang Yuan, Quanjun Lin, Hai-Yi Feng, Yunpeng Zhang, Xing Lai, Mao-Hua Zhu, Jue Wang, Jiangpei Shi, Yanhu Huang, Lele Zhang, Qin Lu, Zeli Yuan, Jonathan F. Lovell, Hong-Zhuan Chen, Peng Sun () and Chao Fang ()
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Yihang Yuan: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Quanjun Lin: SJTU-SM
Hai-Yi Feng: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Yunpeng Zhang: SJTU-SM
Xing Lai: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Mao-Hua Zhu: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Jue Wang: SJTU-SM
Jiangpei Shi: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Yanhu Huang: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Lele Zhang: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Qin Lu: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Zeli Yuan: Zunyi Medical University
Jonathan F. Lovell: State University of New York
Hong-Zhuan Chen: Shanghai University of Traditional Chinese Medicine
Peng Sun: SJTU-SM
Chao Fang: Shanghai Jiao Tong University School of Medicine (SJTU-SM)

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The presence of lymph node (LN) metastases guides cancer staging and worsens prognoses. Incomplete lymphadenectomy of metastatic LNs may end up with disease recurrence, while excessive resection can result in increased postoperative complications with even no survival benefit. Thus, effective non-invasive methods to treat metastatic LNs would be highly desirable. Here, we develop an enzyme-responsive formulation of small-sized doxorubicin-loaded mesoporous silica nanoparticles (DMSN, 40 nm) encapsulated in nanoliposomes (DMSN@Pla-Lipo, 160 nm). The liposomal membrane contains 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), two phospholipids sensitive to secreted phospholipase A2 in human colorectal tumors. In an orthotopic colorectal murine tumor model, phospholipase-induced membrane permeabilization triggers the liberation of DMSN from liposomes for enhanced tumor penetration, conferring an enhanced suppression for the primary tumor. Furthermore, through translocation into metastatic LNs via tumor lymphatics, metastatic tumor cells in LNs are eradicated. Metastases to other major organs are also suppressed, which can be ascribed to the inhibition of colorectal cancer metastasis-associated TGF-β, Wnt, and Hippo signaling pathways in metastatic LNs. The treatment confers an 80% 90-day survival rate in this aggressive tumor model. Taken together, this study demonstrates a deliberate treatment approach for management of both primary tumors and metastatic LNs through multistage drug delivery.

Date: 2025
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DOI: 10.1038/s41467-025-56768-z

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