A lipid/PLGA nanocomplex to reshape tumor immune microenvironment for colon cancer therapy  

作　　者：Nan Zhang Qiqi Sun Junhua Li Jing Li Lei Tang Quan Zhao Yuji Pu Gaofeng Liang Bin He Wenxia Gao Jianlin Chen 

机构地区：[1]Henan Academy of Sciences,Zhengzhou 450046,China [2]National Engineering Research Center for Biomaterials,College of Biomedical Engineering,Sichuan University,Chengdu 610064,China [3]School of Pharmacy,Chengdu University,Chengdu 610106,China [4]School of Laboratory Medicine,Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-origin Food,Chengdu Medical College,Chengdu 610500,China

出　　处：《Regenerative Biomaterials》2025年第1期20-31,共12页再生生物材料(英文版)

基　　金：supported by the National Natural Science Foundation of China[52073216 and 51773130].

摘　　要：Immune checkpoint blockade therapy provides a new strategy for tumor treatment;however,the insufficient infiltration of cytotoxic T cells and immunosuppression in tumor microenvironment lead to unsatisfied effects.Herein,we reported a lipid/PLGA nanocomplex(RDCM)co-loaded with the photosensitizer Ce6 and the indoleamine 2,3-dioxygenase(IDO)inhibitor 1MT to improve immunotherapy of colon cancer.Arginine–glycine–aspartic acid(RGD)as the targeting moiety was conjugated on 1,2-distearoyl-snglycero-3-phosphoethanolamine lipid via polyethylene glycol(PEG),and programmed cell death-ligand 1(PDL1)peptide inhibitor DPPA(sequence:CPLGVRGK-GGG-d(NYSKPTDRQYHF))was immobilized on the terminal group of PEG via matrix metalloproteinase 2 sensitive peptide linker.The Ce6 and 1MT were encapsulated in PLGA nanoparticles.The drug loaded nanoparticles were composited with RGD and DPPA modified lipid and lecithin to form lipid/PLGA nanocomplexes.When the nanocomplexes were delivered to tumor,DPPA was released by the cleavage of a matrix metalloproteinase 2-sensitive peptide linker for PD-L1 binding.RGD facilitated the cellular internalization of nanocomplexes via avβ3 integrin.Strong immunogenic cell death was induced by 1 O2 generated from Ce6 irradiation under 660 nm laser.1MT inhibited the activity of IDO and reduced the inhibition of cytotoxic T cells caused by kynurenine accumulation in the tumor microenvironment.The RDCM facilitated the maturation of dendritic cells,inhibited the activity of IDO,and markedly recruited the proportion of tumor-infiltrating cytotoxic T cells in CT26 tumor-bearing mice,triggering a robust immunological memory effect,thus effectively preventing tumor metastasis.The results indicated that the RDCM with dual IDO and PD-L1 inhibition effects is a promising platform for targeted photoimmunotherapy of colon cancer.

关 键 词：lipid/PLGA nanocomplex immune checkpoint blockade photodynamic therapy IDO inhibition colon cancer 

分 类 号：R73[医药卫生—肿瘤]