Table 1.

Key Examples of Control Over Immune Processing by Tuning Material Properties

Immunological Process to be Controlled	Biomaterial Parameter	Technique/Approach	Biological Outcome	Ref
Targeting to lymphoid organs	Size	Altering organic:water volumetric ratio during flash nanoprecipatiation	20nm NPs rapidly drain to LNs, but 100nm NPs show minimal accumulation	[44]
	Shape	Different NP seeding protocols from aqueous solution	Sphere and star-like particles accumulate in spleen	[47]
	Charge	Addition of cationic or anionic amino acids to the end of displayed antigen peptide sequence	Zwitterionic micelles promotes a combination of LN accumulation and cellular interactions	[49]
	Surface functionalization	PEGylation	Increased active transport of antigen to LNs, decreased ECM interactions with increasing MW of PEG	[50,51]
		Conjugating antigen to targetting moieties	Cell-mediated trafficking of antigen to LNs, enhanced LN accumulation	[56,58,59]
	Elasticity	Electrostatic layer-by-layer assembly, followed by removal of template core to form hollow capsules	Hollow particles can pass through pores up to 4x smaller in size to faciliate LN trafficking	[55]
Targeting APCs	Elasticity	Pickering emulsions	Highly deformable NPs due to raspeberry-like structure of pickering emulsions improves particle interactions with DCs	[67]
		Varying polymer content (i.e. PLGA:PEG ratio)	Stiffer nanodiscs improve uptake by macrophages by increasing material-cell interaction times	[69]
	Charge	Anionic modification of self-assembling polymer chains with different chain lengths of carboxyl group substitution	Intermediate levels of negative charge displays highest level of uptake; highly negatively charged particles are taken less eficiently by cells.	[72]
		Formation of amine containing hydrogels using Particle Replication In Non-wetting Templates (PRINT), followed by protonation/deprotonation of amine groups	In lung, cationic NPs are preferentially taken up by DCs, while anionic NPs are preferentially taken up by macrophages	[74]
	Surface functionalization	Conjugating bacterial sugars or mimics to polymer NP surface	Increased intracellular accumulation targetting endoplasmic reticulum	[75]
	Hydrophobicity	Preparation of dendritic mesoporous organosilica and pure silica NPs	Hydrophobic particles facilitate lysosomal escape for delivery into the cytosol	[78]
	Charge	Altering number of basic amino acid arms on dendrimer	Positively charge NPs can rupture lysosomes to enter cytosol and improve inflammazome activation	[80]
		Functionalization with quarternary ammonium groups to polymer backbone	Positively charged hydrophobic microgels improve membrane disrupting potential to promote cytosolic delivery	[82]
	Controlled Release	Materials selection: polymers with different degradation profiles	Faster release under acidic conditions enhances antigen presentation	[83]
Delivery of Immunostimulatory Cues	Shape	Computationally designed nucleic acid sequences that self-assemble into 2D and 3D structures	Inflammatory cytokine secretion can be tuned based on dimensions (i.e. 2D vs. 3D), and the number of sides on polygonal structures	[91,95]
		Conjugating poorly immunogenic RNA adjuvant to gold NP	Nanorods improve adjuvanticity	[109]
	Controlled Release	Materials selection: polymers degradable by hydrolysis or degraded under acidic conditions	Products of polymer degradation can modulate immune activity	[96–98]
		Alter binding affinity of polymer to TLRa by using softer chained polymers or varying polymer:TLRA ratio	Reduction in adjuvanticity of TLRa with increased interaction strength of polymer carrier	[113,114]
	Surface functionalization (ligand density)	Covalent linking of TLRa at different densities to polymer backbone allowing for chemically defined controlled loading	Higher density induces particle formation and improved activation of DCs and macrophages	[105]
	Topography	Hydrothermal assembly of titanium oxide nanostructural bundles to form nanospikes	Mechanical stress induced by nanospikes activates inflammasome pathway	[107]
Antigen Presentation	Size	Covalent linkage of TLRa to polymers with different chain architectures with distinct hydrodynamic characteristics	Induction of CD8+ T cell responses increases with increasing polymer hydrodynamic radius	[115]
		NPs of different sizes coated with pMHC and anti-CD28 to form aAPCs	Smaller aAPCs require saturated doses of pMHC or artificial magnetic clustering to activate T cells at similar levels compared to larger particles.	[126]
	Controlled Release	Conjugation of antigen to adjuvant using a pH sensitive reversible linker	Release of unmodified antigen improves expansion of T cells	[120]
	Antigen localization	Surface conjugation of antigen and encapsulation of antigen onto polymers	Encapsulated antigens preferentially promote antigen presentation on MHC-I to enhance CD4+ resposnes. Surface conjugated antigens promote antigen presentation on MHC-II, enhancing CD8+ responses	[122–124]
	Surface functionalization	Biotinylated liposomes coated onto mesoprous silica microrods, followed by attachment of anti-CD8 and anti-CD3 antibodies	Fluidity of lipid bilayers allows for robust expnasion of T cells even with lower density of stimulatory cues	[127]
		Site specific binding of antigen to alum via multivalent phosphorylated serine groups that bind hydroxyl groups on alum.	Stable binding of antigen to alum offers conformational control over antigen presentation, allowing for tuning of B cell specificity towards specific antigen epitopes	[134]
	Ligand density	Iron oxide NPs conjugated with pMHC	pMHC must exceed a threshold density for T cell activation to occur	[142]
		Antigen adsorbed to quantum dots	Controlling antigen display to APCs alters T cell responses	[144]
Immune Signal Retention	Controlled Release	Altering linker chemistry (e.g. thioether vs. dssulfide linker) between antigen and polymer	Slower release of antigen prolongs antigen release and antigen presentation over time leading to improved immune response	[147]
		Altering MW and varying degree of cyclic acetal groups on acetylated-dextra MPs	Faster degrading MPs promote strong humoral and cellular responses at earlier timepoints. Slow-degrading MPs drive stronger responses at later timepoints	[150]
	Size	Antigen conjugated to different sized NPs using carbodiimide-mediate coupling to control antigen dose	Larger particles prolong antigen presentation by APCs, resulting in improved antibody production	[148]
		Different gold NP seeding protocols	Retention of 50-100nm NPs on dendrites of FDCs in LNs	[149]
	Surface Functionalization	Peptide conjugated to nucleic acid adjuvant and adsorbed to liposome via hydrophobic anchoring group (cholesterol)	Co-delivery of antigen and adjuvant allows for synchronized peptide presentation and expression of costimulatory markers, improving generation of memory T cells	[152]