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.
Hong Xiao  1  2 ,  Yu Guo  3 ,  Bo Li  2 ,  Xiaoxia Li  2 ,  Yong Wang  1  2 ,  Shisong Han  2 ,  Du Cheng  2 ,  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.
PMID: 32724855 DOI: 10.1021/acscentsci.9b01235
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.

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