Table 2.

Applications of NPs in osteoimunomodulation via modulating macrophage response.

Strategies for Regulating Macrophage Polarization	Applications of NPs in Osteoimunomodulation	References
Intrinsic properties	Gold, TiO2, and cerium oxide (CeO2) NPs can enhance M2 polarization.	[116,117,118]
Nanopore structure and pore size	NPs with pores of larger size (100 and 200 nm) were highly anti-inflammatory and inhibited M1 polarization.	[119]
	The nanoneedle structure induced M2 polarization. The micropattern sizes of 12 μm and 36 μm in the micro/nano hierarchy enhanced M2 polarization.	[120]
Surface roughness	Ti with smooth surface stimulated M1 activation. Ti with rough surface enhanced M2 polarization.	[122]
Composition	Gold NPs fused hexapeptides Cys-Leu-Pro-Phe-Phe-Asp, peptide arginine-glycine-aspartic acid (RGD), and IL-4 could stimulate M2 polarization.	[112,126,127]
	CeO2 NPs with hydroxyapatite could enhance M2 polarization.	[128]
	Strontium (Sr)- or copper (Cu)-doped bioactive glass particles promoted M2 polarization and enhanced osteogenesis.	[124,125]
Drug delivery	Various nanocarriers have delivered IL-4 (anti-inflammatory cytokine) to induce M2 polarization.	[131,132,133]
	NPs can deliver S1P synthetic analog to direct macrophage polarization toward M2.	[134]
	CD163 gene has been encapsulated into polyethyleneimine NPs decorated with a mannose ligand to induce CD163 expression and macrophage polarization toward M2.	[137]
	miR-223 5p mimic was delivered to induce macrophage polarization to M2.	[138]
	Resolvin D1-loaded gold nanocages (AuNC) were coated with M1-like macrophage membranes to enhance M2 polarization.	[139]
A sequential release of therapeutics induces the M1-to-M2 phenotype switch during tissue regeneration.	Spillar et al. designed a scaffold that achieved a sequential release of first IFN-γ and then IL-4 to modulate macrophage polarization from early stage M1 to later-stage M2.	[142]
	NPs carry both miRNA-155 and miRNA-21 to sequentially stimulate macrophage polarization first toward M1 and then the M2 phenotype.	[146]
	Microcrystalline bioactive glass scaffolds with different doses of ZnO orchestrate the sequential M1-to-M2 macrophage polarization.	[149]
	Sr-substituted nanohydroxyapatite (nano-SrHA) coatings and IFN-γ to the surface of native SIS membrane control a sequential M1-M2 macrophage transition.	[150]