Background: Among the many immunosuppressive cells in the tumor microenvironment, tumor-associated-macrophages (TAMs) are well known to contribute to tumor development. TAMs can be conditioned (polarized) to transition between classical M1-like macrophages, or alternatively to M2-like macrophages. Both are regulated by signaling molecules in the microenvironment. M1-like TAMs can secrete classic inflammatory cytokines that kill tumors by promoting tumor cell necrosis and immune cell infiltration into the tumor microenvironment. In contrast, M2-like TAMs exhibit powerful tumor-promoting functions, including degradation of tumor extracellular matrix, destruction of basement membrane, promotion of angiogenesis, and recruitment of immunosuppressor cells, all of which further promote tumor progression and distal metastasis. Therefore, remodeling the tumor microenvironment by reversing the TAM phenotype will be favorable for tumor therapy, especially immunotherapy.

Immunosuppression and immune tolerance lead tumor cells to evade immune system surveillance and weaken drug efficacy. The presence of various immunosuppressive cells in the tumor microenvironment, especially tumor-associated macrophages (TAMs), has been shown to be a driving force in tumor initiation and development. Reversion of the TAM phenotype is an effective way to induce a subsequent antitumor immune response. In this study, we developed baicalin-loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles containing an antigenic peptide (Hgp 100_25–33, Hgp) and a toll-like receptor 9 agonist (CpG). The nanoparticles were further coated with a galactose-inserted erythrocyte membrane, which actively targeted the TAMs. The TAM polarization and tumor treatment effectiveness of the nanoparticles were evaluated. The biomimetic nanoparticles showed enhanced cell uptake in vitro and targeted effects in vivo. In addition, compared with baicalin-loaded PLGA-NPs (B@NPs), the biomimetic nanoparticles, such as Hgp/B@NPs-CpG and NPs@RBC-Gala, significantly polarized the TAMs such that they changed from the M2 type to the M1 type both in vitro and in vivo. Subsequently, the infiltration of CD4⁺ T and CD8⁺ T cells into tumor sites after being induced by the biomimetic nanoparticles was greatly increased, which suggested a significant enhancement of the immune activation effect and T cell response. In addition, the activation of the T cells and induction of the CTL responses effectively suppressed melanoma tumor growth in vivo. In conclusion, the biomimetic nanoparticles effectively reversed the TAM phenotype from M2 to M1, which further improved the tumor immune microenvironment and promoted tumor immunotherapy. These results suggested that the TAM-targeted biomimetic drug delivery system had the potential to reverse the phenotypes of TAMs contributing to reverse the immunosuppressive tumor microenvironment and promote tumor treatment.