Precise Delivery of Nanomedicines to M2 Macrophages by Combining “Eat Me/Don’t Eat Me” Signals and Its Anticancer Application

Abstract

Targeted delivery of nanomedicines to M2 tumorassociated macrophages (TAMs) has been proposed to reduce tumor promotion and enhance the efficacy of anticancer therapy. However, upregulated receptors on M2 TAMs are also expressed on M1 TAMs and other macrophages in normal tissues. Therefore, improving targeting specificity remains a key challenge. Here, we developed a precise M2 TAM-targeted delivery system using "eat-me" and "don't-eat-me" signals. A CD47-derived self-peptide ligand (don't-eat-me signal) and galactose ligand (eat-me signal) were introduced on liposomes. Cleavable phospholipid-polyethylene glycol was covered on the surface and could combine with the self-peptide to inhibit macrophage recognition even after immunoglobulin M adsorption and protect galactose from hepatic clearance to prolong the circulation time and promote the accumulation of liposomes in tumors. This detachable polymer can be removed by the redox microenvironment upon transcytosis through the tumor endothelium and re-expose the self-peptide and galactose. The self-peptide highly reduced M1 macrophage phagocytosis, and the galactose ligand enhanced the interaction between the liposomes and M2 macrophages. Thus, the modified liposomes enabled specific recognition of M1/M2 TAMs. In vitro evidence revealed reduced endocytosis of the liposomes by M1 macrophages. Moreover, in vivo studies demonstrated that doxorubicin-loaded liposomes efficiently eliminated M2 TAMs but did not affect M1 TAMs, enhancing the potency of the antitumor therapy. Collectively, our results demonstrate the potential of combining active escape and active targeting for precisely delivering a drug of interest to M2 macrophages and suggest its application in anticancer therapy.

Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review

“…siRNAs with βglucose shells targeting the dectin-1 receptor of macrophages have been successfully designed for oral treatment of systemic inflammation (Puig-Kröger et al, 2009). In a recent study, liposomes were functionalized with CD47-derived auto peptides and galactose in combination with carriers of "eat me/not eat me" signals to precisely deliver nanomedicines to M2 macrophages (Tang et al, 2021). Last but not the least, most reported scavenger receptors are highly expressed by phagocytes including macrophages.…”

Role of CD47-SIRPα Checkpoint in Nanomedicine-Based Anti-Cancer Treatment

“…As previously mentioned, the effect of CRT exposure, serving as an “eat me” signal, is considered to be counterbalanced and potentially dampened by CD47 expression ( Chao et al, 2010a ). Moreover, the upregulated expression of CD47 on the surface of tumor cells makes it an active targeting site for tumor cells, facilitating nonspecific distributed ICD inducing drugs to target tumor tissues and reduce systemic toxicity ( Tang et al, 2021 ). Therefore, codelivery, which simultaneously removes an inhibitory signal and introduces an activating signal, can produce an enhanced antitumor effect ( Abdel-Bar et al, 2021 ; Lee et al, 2021 ).…”

“…The CD47 protein, as a “self” marker, can evade phagocytosis by the CD47-SIRPα interaction ( Logtenberg et al, 2020 ). With regard to the pivotal role of CD47 in the regulation of immune responses, the present paper outlines emerging methods for the production of bioinert biomaterials and NPs using CD47 ( Gheibi Hayat et al, 2019 ; Figure 4 ) Examples of stealth functionalization by CD47 mimicry utilized for antitumor nanomedicine are listed in Table 4 ( Kamerkar et al, 2017 ; Shim et al, 2017 ; Jiang et al, 2018 ; Song et al, 2019 ; Wang et al, 2019 ; Belhadj et al, 2020 ; Cheng et al, 2021 ; Tang et al, 2021 ; Xie et al, 2021 ; Zhang et al, 2021 ). For instance, Tang et al designed a precise delivery nanomedicine to M2 macrophages by combining “eat me/don’t eat me” signals and verified its role in antitumor therapy in an A20 subcutaneous tumor mouse model.…”

“…Therefore, this nanocarrier can precisely target M2-type TAMs. In addition, DOX loaded into liposomes further enhances its antitumor effect ( Tang et al, 2021 ; Figure 5 )…”

Protein-Crowned Micelles for Targeted and Synergistic Tumor-Associated Macrophage Reprogramming to Enhance Cancer Treatment

“…In general, macrophages can be polarized to a M1 or M2 phenotype, in which the immunostimulatory M1 phenotype has the ability to combat tumors. However, TAMs are thought to more closely resemble M2-type macrophages (immunomodulatory phenotype), which promote tumor progression by stimulating angiogenesis, invasion, and metastasis, protect tumor cells against chemotherapy, and suppress antitumor immune response. − TAMs are now being recognized as the potential biomarkers for the diagnosis and prognosis of cancers. − Therefore, TAM-targeted therapy represents an attractive kind of cancer treatment.…”