Table 2.

Synthetic NP-ISV platforms, mechanisms, and treatment approaches for anti-tumor immunity Induction

NP Formulation	Unique Immune Activating Aspects	Combination Therapy	Ref
Loaded-Mesoporous Silica NP (80 nm) + Magnetic NP-coated Silica NP (100 nm)	• Dual NP-approach. • Silica NP contained ICG (acts as PTT agent and TLR-7 agonist) + YM155 (survivin inhibitor); • Magnetic-coated silica NPs were combined with aCD-47 • IL-6↑, IL-12↑, TNF-α↑, CD4+ and CD8+ cells in distant tumors↑, mature DC↑	TLR, PTT, TH	155
Maleimide-PEG PLGA NP (167 nm)	• NPs conjugated with aPD-1 and aOX40 for induction of maximum T cell activation in B16F10 and 4T1 models, 5/6 survived rechallenge (i.v. injection)	CBT	15
Antigen-capturing PLGA NP (initial size <200 nm; changed after antigen capture)	• Used different coatings (e.g., DOTAP, NH2-PEG, mPEG, Maleimide) in lethally irradiated ex vivo B16F10 cells to quantify antigen capture. Combined with aPD-1 immunotherapy to induce abscopal effect	CBT, RT	156
PLGA photothermal (PTT) NPs (100 nm)	• Loaded with ICG (PTT agent and TLR-7 agonist), +/− aCTLA-4) • Induced DC maturation, IL-6↑, IL-12↑, TNFα↑ in 4T1 and CT26 models (intratumoral-NP, i.v.-CBT); NP+PTT+CBT increased the CD8+ TIL↑ (~19.7%) from NP+CBT alone (8.96%)	TLR, CBT, PTT, TH	119
PANI-GSC polymer Loaded-160 (~NP nm)	• Loaded with R848 (NIR agent and TLR-7/8 agonist) in CT26 model • CD3+ infiltration↑, Granzyme B↑, Hsp70↑, IL-6↑, IL-10↓, apoptosis↑, MDSCs↓	TLR, PTT, TH	118
CRT-Loaded-DOTAP Liposome (~230 nm)	• CRT-loaded, DOTAP-derived liposomes encapsulated with CRT plasmid in combination with high intensity focused ultrasound (HIFU) in B16F10 model • ICD↑, CRT surface expression↑, 4.5-fold increase in M1/M2 ratio, Granzyme-expressing CD3+CD8+ and CD4+ T cells↑, PD-1 CD8+ T cells↑, increased resistance to rechallenge	HIFU	62
Citrate-coated SPION (58 nm)	• EL4 T lymphocytes from mouse lymphoma were loaded with SPIONs and successfully targeted via AMF while keeping toxicity to T cells minimal • Potential to be used in future with CAR T-cell therapies • In vitro experiment	AMF	157
Dendritic mesoporous organosilica NP (~210 nm)	• Loaded with Cu2+ ions that acted as Fenton’s reagents. DOX and tetrasulfide groups collectively increased the ROS production intratumorally, depleted tumoral GSH and increased serum IFNγ in a 4T1 model • aPD-L1 was combined to synergistically increase efficacy and drastically increase serum TNF-α and CTL in distant tumor tissue	Other, CBT	91
PLGA-PEG-GRGDS peptide shell loaded-NP (~218 nm)	• Loaded with aPD-1, iron oxide NPs and perfluoropentane (PFP) in B16F10 model • Serum IL-6↑ (72h post trt), serum IFN-γ↑ (72,168h post trt), TNF-α↑ (72,168h post trt), TIL↑	CBT, TH	154
Polyacrylamide hybrid nanogel (~30 nm)	• Incorporated with gold NPs (3–7 nm) and methotrexate or folic acid • Achieved enhanced killing of KB tumor cells in a concentration-dependent manner while avoiding toxicity or retention in macrophages • Coating gold NPs in either folic acid or methotrexate was found to preserve macrophages	Other	158
Loaded-CaCO3 NP (~100 nm) as in-Situ Hydrogel	• Loaded with aCD-47 as a “Bioresponsive immunotherapeutic spray” for post-resection • Showed macrophage polarization, decreased TME acidity and increased antigen presentation in B16 models	Other	90
Iron-oxide NP (110 nm) + CPMV VNP+ RT	• Combined AMF-Iron-oxide NPs with CMPV VNPs and radiation in canine oral melanoma • Observed increased adjuvanticity, immune cell infiltration and multiple patients fully resolved treated tumor	TH, AMF, RT	134
Magnetite Cationic Liposome (10 nm)	• Magnetic NP + AMF were studied in MM46 mouse mammary carcinoma tumor model • Single round of hyperthermia (three times in 24h intervals) was effective against 7 mm tumors but not 15 mm tumors, cured mice displayed acquired antitumor immune memory	TH, AMF	159
Polydopamine-coated Al2O3 NPs (~280–340 nm) + CpG	• 50 % of mice achieved tumor eradication and survived for 120 days (endpoint of experiment); Median survival was 3.9- and 6.3- fold longer in combination NP+CpG group than controls • Al2O3 showed marked increase in heating-reaching 55 C within 5 min • Combination treatment caused increases in serum levels of mice TNF-α and IFN-γ at 24, 48, 72 h and 1 week post treatment in vivo	PTT, TH (ablation), TLR	160
Chitosan-coated Hollow Copper Sulfide NPs (~85 nm HCuSNPs after PTT break into ~10 nm CuS NPs) + CpG	• This “photothermal immunotherapy” approach- increased mature myeloid dendritic cells in tumor by 41-, 5.8- and 14.2-fold compared to control, NP+CpG alone and NP+GpC(CpG control)+laser • Treatment increased IFN-γ-secreting CD8+ T cells in secondary tumors by 19-fold when compared to control and decreased distant tumor growth	PTT, TH (ablation), TLR	82
CpG-coated Prussian Blue NPs (Cubic particles ~50 nm, hydrodynamic size ~92 nm)	• CpG-NP construst was shown to stay intact between pH 4.6–7.0 for up to 4 days even after PTT, so the adjuvanticity of intratumoral CpG is maintained • Caused significantly decreased intracellular ATP, and markedly increased levels of calreticulin and decreased levels of intracellular HMGB1 in vitro- indicating ICD • Observed enhanced long-term survival and immune protection against re-challenge in Neuro2a model of neuroblastoma in mice	PTT, TH (ablation), TLR	161
Magnetite cationic liposomes (magnetite-10 nm, total size-unlisted) + recombinant heat shock protein 70	• Formulation observed efficient specific heating via AMF, and some systemic antitumor immunity seen via splenic lymphocytes from cured mice showed greater anticancer effects in B16 cells • Survival was significantly extended and 20% of mice displayed complete tumor regression within 14 days	TH, AMF, Other	162
APTES-modified-Fe3O4NP/CpG particles (FeNP-10 nm, total construct-50 nm) (APTES- 3-aminopropyltriethoxysilane)	• Tested in C26 colon cancer and 4T1 breast cancer models in vivo • In C26 cells, FeNP/CpG groups showed 8.2-fold more tumor-killing activity than control and 9.7-fold and 1.7-fold more than FeNP and CpG groups; 4T1 cells, FeNP/CpG 7.4-fold higher than control and 6.6-fold and 1.4-fold more than FeNP and CpG via 51 Cr release assay ex vivo • Formulation is primarily viewed as potential vehicle for non-viral gene delivery and enhanced transfection efficiency- since enhanced CpG into DCs is shown	Other	163
Bionized nanoferrite(BNF)-starch coated Iron oxide (Fe2O3) NPs (100 nm)	• Increase by over 10-fold of CXCL2, CCL3, CXCL5 between heated and non-heated groups • Observed that local hyperthermia of 43 C for 30 min activated DCs in draining lymph nodes and increases CD8+ T cells, and efficacy is CD8+-dependent • Interestingly, observed better primary tumors when treated, led to greater immunity and resistance to rechallenge; also, saw no immunity developed in 45 C treatment despite more primary tumor cells being destroyed	AMF, TH	164
Perfluorotributylamine (PFTBA) NPs (~150–200 nm)	• Observed >10-fold change in clot weight from PFTBA as platelet inhibitor in vitro and decreased platelet adhesion, aggregation and granule secretion, measure by ATP, 5-HT and angiopoietin-1 • Increased tumor infiltration of RBCs and tagged-lymphocytes supports that PFTBA enhanced tumor vessel permeability via platelet inhibition in CT26 tumors • Enhanced lymphocyte tumor infiltration by PFTBA NPs was combined with CBT (anti-PD-L1) to observe drastic decreases in tumor weight/volume and significant increases in IFN- γ, IL-6, TNF-α along with ~3.5-fold, ~6.5-fold and ~6.5-fold increases in tumor infiltrating-CD45+, CD4+ and CD8+ T cells, respectively.	CBT, Other	165

^*TLR- Toll-like receptor, CBT, PTT- Photothermal therapy, TH- Targeted hyperthermia, AMF- Alternating magnetic field, HIFU- High Intensity Focused Ultrasound, RT- Radiotherapy, chemotherapy TH*- Targeted Hyperthermia from heat-shocked cells, but not included in treatment regimen, ICG- indocyanine green, PFP- perfluoropentane