Nanodrugs Incorporating LDHA siRNA Inhibit M2-like Polarization of TAMs and Amplify Autophagy to Assist Oxaliplatin Chemotherapy against Colorectal Cancer
Lijun Hu, Sicong Huang, Gengjia Chen, Bo Li, Li Tan, Minzhao Lin, Yongquan Huang, Zecong Xiao, Xintao Shuai, Zhongzhen Su
Abstract
Oxaliplatin (OXA) is a first-line chemotherapeutic agent for treating colorectal cancer (CC). However, the chemotherapeutic effect of OXA on CC is limited by the M2-like polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) and protective autophagy of tumor cells. Here, a cationic polymer APEG-PAsp(PEI) (PAPEI) was prepared to deliver small-interfering RNA (siRNA) to silence the lactate dehydrogenase A (LDHA) gene (LDHA-siRNA) to enhance the chemotherapeutic effect of OXA on CC. The PAPEI/LDHA-siRNA nanocomplex effectively silenced the LDHA gene to inhibit the secretion of lactic acid from tumor cells, resulting in inhibition of the M2-like polarization of TAMs. In addition, the nanocomplex also amplified OXA-induced autophagy and transformed protective autophagy into autophagic death. Consequently, the combination treatment of OXA and PAPEI/LDHA-siRNA showed a dramatically increased chemotherapeutic effect on CC compared with the OXA-alone treatment, which also suggested its attractive potential for treating CC-like immune "cold" tumors.