Nanomaterials modulating TAMs polarization for the treatment of HCC via the NF-κB signaling pathway.(A) TLR. (1) Under NIR irradiation, EcNflaB-UCNPs released flaB. FlaB binds to TLR5, activates the NF-κB signaling pathway, and promotes M2-type TAM polarization to the M1-type. (2) PLDX-PMI was composed of PCN-Len NPs and p (Man-IMDQ) NRs. p (Man-IMDQ) NRs release IMDQ, promote TLR7, and then activate the NF-κB signaling pathway, promoting M2-type TAM polarization to M1-type. PCN-Len NPs released Len, thereby inhibiting VEGFR in vascular endothelial cells and reducing tumor microvessel density., (3) NPs (SOR/R848) released SOR and R848-C16. SOR causes apoptosis in HCC cells, and R848-C16 promotes TLR7, thereby promoting M2-type TAM polarization to the M1 type., (4) MOF-CpG-DMXAA promotes the cGAS-STING–NF–κB pathway through TLR4 and promotes M2-type TAM polarization to M1-type, (5) DL@NP-M-M2 pep promotes M2-type TAM polarization to M1-type via TLR2 and TLR9, regulating PPAR-γ and NF-κB(B) AMP, (1) Met@Man-MPs target M2-type TAMs via Man, releasing Met and promoting AMP production. AMP activates AMPK and initiates NF-κB-mediated transcription, promoting M2-type TAM polarization to the M1-type, (2) C60(OH)x increases Arg and Acp activities in TAMs and promotes TNF-α secretion. Acp activity may reflect changes in AMP levels(C) IKKβ. The CMCS/M-IMD-CLN released CLN through H+ ions in the TME. CMCS and M-IMD target HCC cells and M2-type TAMs, respectively, releasing SOR and IMD-0354. SOR induces the apoptosis of HCC cells. IMD-0354 inhibits IKKβ, thereby inhibiting IκB phosphorylation and NF-κB-mediated transcription and increasing the content of M1-type TAMs(D) Positive role of ROS, (1) PIONs@E6 releases IONPs, generates ROS through the Fenton reaction, and activates the NF-κB signaling pathway to promote TAM polarization to M1-type. (2) Man-IONPs target M2-type TAMs through Man, release IONPs, increase the content of ROS in cells, and promote TAM polarization to the M1 type.(E) Negative role of ROS. Nanoliposome C6-Ceramide can inhibit the ROS of macrophages, effectively reduce the number of M2-type TAMs, and increase the number of M1-type TAMs in tumor tissues. TAMs, Tumor-associated macrophages; HCC, Hepatocellular carcinoma; NF-kB, Nuclear factor-kappaB; TLR, Toll-like receptor; Near-infrared, NIR; EcNflaB-UCNPs, Lanthanide upconversion nanoparticles-conjugated engineered Escherichia coli Nissle 1917; FlaB, Flagellin B; PLDX-PMI, p (Man-IMDQ) NRs encapsulated in PCN-Len/DX hydrogel; p (Man-IMDQ) NRs, p (Mannose-imidazoquinoline) nanoregulators; IMDQ, Imidazoquinoline; PCN-Len NPs, lenvatinib-loaded nanomedicines; Len, Lenvatinib; VEGFR, Vascular endothelial growth factor receptor; NPs (SOR/R848), Nanoparticles (Sorafenib/Resiquimod); SOR, Sorafenib; R848-C16, Modified resiquimod; MOF-CpG-DMXAA, Metal-organic framework-801-cytosine-phosphate-guanine oligodeoxynucleotides −5, 6-dimethylxanthenone-4-acetic acid; cGAS, cyclic GMP-AMP synthase; STING, Stimulator of interferon genes; DL@NP-M-M2 pep, Lactide-glycolide copolymer nanoparticles to load d-lactate, and modified the DL-loaded NP with HCC membrane and M2 macrophage-binding peptide; PPAR-γ, peroxisome proliferator–activated receptor γ; STAT, Signal transducer and activator of transcription; PI3K, Phosphoinositide 3-kinase; AKT, AGC serine/threonine kinases; AMP, Adenosine monophosphate; AMPK, AMP-activated protein kinase; Met@Man-MPs, Metformin encapsulated to Mannose-cellular microparticles; Arg, Arginine; Acp, Acid phosphatase; TNF-α, Tumor Necrosis Factor-α; CLN CMCS/M-IMD-CLN, Cationic lipid-based nanoparticles o-carboxymethyl-chitosan/Mannose- Imiquimod- Cationic lipid-based nanoparticles; CLN, Cationic lipid-based nanoparticles; CMCS, O-carboxymethyl-chitosan; M-IMD, Mannose- Imiquimod- Cationic lipid-based nanoparticles; IKKα, IkappaB kinase α; IKKβ, IkappaB kinase β; IκB, NF-κB inhibitor; ROS, reactive oxygen species; PIONs@E6, Exosomes synergized with pegylated IONs loaded with chlorin E6; IONPs, Iron oxide nanoparticles; Man-IONPs, Mannose- Iron oxide nanoparticles; Man, Mannose
