M2-Like Tumor-Associated Macrophage-Targeted Codelivery of STAT6 Inhibitor and IKKβ siRNA Induces M2-to-M1 Repolarization for Cancer Immunotherapy with Low Immune Side Effects

Hong Xiao; Yu Guo; Bo Li; Xiaoxia Li; Yong Wang; Shisong Han; Du Cheng; Xintao Shuai

doi:10.1021/acscentsci.9b01235

M2-Like Tumor-Associated Macrophage-Targeted Codelivery of STAT6 Inhibitor and IKKβ siRNA Induces M2-to-M1 Repolarization for Cancer Immunotherapy with Low Immune Side Effects

ACS Cent Sci. 2020 Jul 22;6(7):1208-1222. doi: 10.1021/acscentsci.9b01235. Epub 2020 Jul 1.

Authors

Hong Xiao^{1

2}, Yu Guo³, Bo Li², Xiaoxia Li², Yong Wang^{1

2}, Shisong Han², Du Cheng², Xintao Shuai^{1

2}

Affiliations

¹ College of Chemistry and Materials Science, Jinan University, Guangzhou 510632, China.
² PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China.
³ Department of Oncology and General Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.

Abstract

Tumor-associated macrophages (TAMs) usually display the tumor-promoting M2 phenotype rather than the tumoricidal M1 phenotype. Thus, M2-to-M1 repolarization of TAMs has emerged as a promising strategy for tumor immunotherapy nowadays. However, immune side effects remain a great challenge, because phenotypic conversion of macrophages into the proinflammatory M1 phenotype may also be induced in normal tissue. Here, aiming at repolarizing TAMs without altering the M1/M2 polarization balance in healthy organs, we develop a micellar nanodrug with M2-targeting peptides (M2peptide) hidden in the pH-sheddable PEG corona so that an active targeting of M2-like macrophages is triggered only in the acidic tumor microenvironment (TME). The smart nanodrug effectively functions M2-to-M1 repolarization via M2-targeted codelivery of IKKβ siRNA and STAT6 inhibitor AS1517499 (AS), which suppresses the tumor growth and metastasis. Moreover, immune side effects are reduced because the neutral-pH environment in healthy organs does not trigger a "stealth-to-nonstealth" conversion of the nanodrug essential for M2-targeted drug delivery.