Emerging Nanomaterials for Cancer Immunotherapy

Purpose: Conventional cancer immunotherapies (checkpoint inhibitors, CAR T cells) are effective but expensive, cause adverse side effects, and face challenges in solid tumours. Nanomaterials offer advantages in delivery, diagnostics, and immune modulation, but a comprehensive understanding of how different nanomaterial types (organic, inorganic, cell membrane-based) can be integrated into cancer immunotherapy—and how their biodistribution and toxicity profiles affect clinical translation—remains needed. ---

Hypothesis: The review’s central thesis is: if nanomaterials (lipids, polymers, metals, cell membranes) are surface-engineered with ligands, antigens, or antibodies, then they can effectively deliver immunomodulatory payloads—checkpoint inhibitors, cytokines, antigens, adjuvants, and small molecules—to target immune cells, enhance antitumour immunity, and overcome limitations of conventional cancer immunotherapy. ---

Aims: - Review conventional cancer immunotherapy and its limitations. - Discuss emerging organic and inorganic nanomaterials for cancer immunotherapy, including liposomes, polymeric nanoparticles, plasma membrane vesicles, viral-mimicking particles, and metal-based nanoparticles. - Summarize nanomaterial-mediated delivery of peptides/antigens, cell membranes, checkpoint inhibitors, and small molecules. - Discuss biodistribution challenges, safety concerns, and the gap between animal models and human cancer immunology. - Summarize ongoing clinical trials of nanomaterial-based cancer immunotherapy. ---

Delivery system: Organic nanomaterials: - Liposomes: cationic liposomes (DOTAP, DOTMA), PEGylated liposomes, lipid microbubbles; payloads include OVA peptide, TRP2 peptide, α-GalCer adjuvant, mRNA lipoplexes, anti-CD40, CpG. - Polymeric nanoparticles: PLGA, PEG-PLL-PLLeu (PMP), Ac-DEX (acetylated dextran), chitosan, PPS (polypropylene sulfide), PEI derivatives; payloads include antigens, CpG-ODN, STAT3 siRNA, TLR agonists, ICG, R837 (imiquimod). - Plasma membrane vesicles (PMVs): derived from cancer cells, dendritic cells; display GPI-HER2, GPI-B7-1, GPI-IL-12; deliver tumour antigens. - Viral-mimicking protein nanoparticles: pyruvate dehydrogenase E2 protein nanoparticles; CpG + gp100 epitope. - Dextran nanoparticles: mannose receptor-targeting OVA-DEX, Ac-DEX. Inorganic nanomaterials: - Gold nanoparticles (AuNPs): AuNP@B16F10, AuNP@DCB16F10; photothermal therapy; CpG conjugation. - Iron oxide–zinc oxide core-shell nanoparticles: deliver CEA to DCs; MRI tracking. - Mesoporous silica nanoparticles (MSNPs): Au-XL-MSN with CpG; PEI-coated MSNP with curcumin; GPC3-targeting CAR-T cell membrane-coated MSNP with IR780. - Prussian blue nanoparticles (PBNPs): anti-CTLA-4 delivery. - Copper sulfide (CuS) nanoparticles: LPS-coated, photothermal therapy. - Upconversion nanoparticles (UCNPs): PEG, Ce6, R837, anti-CTLA-4. - Zinc pyrophosphate (ZnP) nanoparticles: pyrolipid, anti-PD-L1. Cell membrane-based nanomaterials: - Cancer cell membrane-coated PLGA nanoparticles (CCNPs) - NK cell membrane-coated nanoparticles (TCPP-loaded) - RBC membrane-coated nanoparticles - Platelet membrane-coated nanoparticles - Neutrophil membrane-coated nanoparticles - Leukocyte membrane-coated microspheres Payloads: Peptides, antigens (OVA, TRP2, gp100, CEA, HER2), adjuvants (CpG, R837, MPLA, α-GalCer), antibodies (anti-CTLA-4, anti-PD-L1, anti-CD40), small molecules (imiquimod, JSI-124, SD-208), siRNA, mRNA, photosensitizers (ICG, Ce6, ZnPc, HPPH), chemotherapeutics (cisplatin, paclitaxel). Targeting ligands: Mannose, folate, tLyp1 peptide (Nrp1), anti-CD40, anti-CTLA-4, anti-PD-L1, HER2 scFv, octreotide (SSTR). ---

Approach: Narrative review of preclinical and clinical literature. No primary experimental groups. Model systems discussed include: - In vitro: BMDCs, DCs, T cells, B16-F10 melanoma, CT26 colorectal cancer, 4T1 breast cancer, Hepa1-6 hepatocellular carcinoma, MCF-7 breast adenocarcinoma, Huh-7 hepatocellular carcinoma. - In vivo: C57BL/6 mice, BALB/c mice, patient-derived xenograft (PDX) models; tumour models including melanoma, colorectal, breast, hepatocellular, pancreatic, neuroblastoma, and lymphoma. - Clinical trials: Phase I, II, III trials of nanomaterial-based cancer immunotherapies (Table 2 lists NCT numbers including NCT04033354, NCT03719326, NCT02620865, NCT04484909, NCT03589781, NCT03382340). - Disease context: Haematological malignancies and solid tumours. ---

Key methods: Techniques and endpoints highlighted across cited studies: - Flow cytometry for DC maturation (CD86, CD40, MHC II), T cell proliferation (CD4+, CD8+), cytokine secretion (IFN-γ, TNF-α, IL-12, IL-2). - Confocal microscopy for cellular uptake and antigen presentation. - MRI for in vivo nanoparticle tracking. - ELISA for antibody titres (IgG1, IgG2a) and cytokines. - In vivo tumour growth inhibition, survival analysis, metastasis assessment. - Cytotoxicity assays (CTL responses, NK cell activity). - Photothermal/photodynamic therapy efficacy assessment. - Biodistribution and pharmacokinetic studies. ---

Key results: - Cationic liposomes with α-GalCer and TRP2: Enhanced IFN-γ secretion, cytotoxic T-cell activation, and reduced tumour survival; PEG-coating reduced cytotoxicity. - PLGA nanoparticles with TLR ligands and antigen: Improved antibody and T-cell responses compared to soluble antigen plus adjuvants, resembling live viral vaccine immunogenicity. - Pyruvate dehydrogenase E2 nanoparticles with CpG and gp100: 1.5-fold increase in CD8+ T cells and 5-fold increase in IFN-γ compared to unbound peptide and CpG; 40% increase in survival time. - AuNP@DCB16F10: Promoted DC maturation, cytokine secretion, T cell activation; inhibited tumour metastasis and relapse. - Iron oxide–zinc oxide core-shell nanoparticles: Delivered CEA to DCs; significant reduction in tumour growth and sustained survival in C57BL/6 mice. - CAR-NK cells (clinical trial NCT03056339): 8/11 patients responded; 7 complete remissions (4 lymphoma, 3 CLL) within 30 days; no cytokine release syndrome or neurotoxicity. - ICG-R837 PLGA nanoparticles + anti-CTLA-4: Inhibited tumour growth and metastasis; activated and matured DCs at tumour site. - Pathogen-mimicking magnetite nanoparticles + anti-PD-L1: 100% tumour rejection in aggressive B16-F10 murine melanoma. - Sipuleucel-T (NCT00065442): Prolonged survival in metastatic castration-resistant prostate cancer (341 patients vs 171 placebo); adverse effects included chills, fever, headache. ---

Interpretation: The authors conclude that nanomaterials are promising entities to enhance cancer immunotherapy, particularly biological nanomaterials due to their unique characteristics and functions. Nanoparticles can serve as immune stimulators or adjuvants, deliver peptides/antigens/whole cell membranes, target checkpoint inhibitors, and reverse the immunosuppressive TME. Preclinical and clinical trial outcomes motivate further clinical testing. However, challenges remain, including inadequate knowledge of patient and TME heterogeneity and lack of animal models that faithfully impersonate human cancer immunology. Overcoming these challenges would expand the field of immune-oncology and facilitate new cancer immunotherapy approaches. ---

Limitations: - Biodistribution challenges: Serum protein binding (opsonization) enhances macrophage engulfment and causes significant payload loss; RES clearance limits circulation time. - Safety concerns: Nanoparticles can induce or inhibit innate immune responses; phase transformations, aggregation, surface reconstruction, and dissolution may provoke immunotoxic effects. - Animal model disparities: Significant differences exist between human cancer immunology and animal models (APC composition, T/B cell presence, tumour antigens, immune modulation complexity). - Clinical translation barriers: Variability in patient characteristics, TME, and tumour type; drug screening, dosing, and administration protocols require optimization. - CAR T cell limitations: Toxicity, complex production, high cost, and poor efficacy against solid tumours. - Small molecule limitations: Development lags behind monoclonal antibodies due to challenges in formulating molecules to occupy the hydrophobic PD-1/PD-L1 interface with high affinity. - As a review: Not a systematic review or meta-analysis; no primary data.