Cell-Based Delivery Systems: Emerging Carriers for Immunotherapy

Purpose: Immunotherapy has limited response rates and systemic side effects, and synthetic drug delivery systems can be immunogenic and toxic. Cell-based delivery systems—using endogenous cells as natural carriers—offer low immunogenicity, low toxicity, improved biocompatibility, active tissue targeting, and the ability to cross biological barriers. This review surveys the design principles and immunotherapeutic applications of cell-based delivery systems for cancer, autoimmune diseases, and infectious diseases. ---

Hypothesis: The central thesis is: if endogenous cells (or their membranes/derivatives) are engineered as delivery carriers, then they can shuttle immunotherapeutics to desired sites with spatiotemporal control, enhance treatment efficacy, and reduce systemic side effects compared with synthetic delivery systems. ---

Aims: - Survey the latest research progress on cell-based delivery systems. - Discuss different cell types used as carriers: RBCs, platelets, neutrophils, T cells, DCs, macrophages, NK cells, stem cells, cancer cells, cell membranes, extracellular vesicles, subcellular organelles, and bacteria. - Summarize critical design and modification principles: cell surface modification, cell conjugation, cell membrane wrapping, and genetic engineering. - Highlight emerging immunotherapeutic applications in cancer, autoimmune diseases, and infectious diseases, and discuss translation potential and limitations. ---

Delivery system: Cell-based carriers: - Red blood cells (RBCs): long circulation (~3 months), CD47 “self” marker, lung targetability, large surface area, no nucleus/organelles. - Platelets: inflammation/wound/tumor homing, P-selectin, CD47, CD55, CD59; circulation ~8–9 days. - Neutrophils: chemotaxis to inflammation, can cross blood–brain barrier, release NETs. - T cells: CAR-T, IL-8 receptor-modified CAR-T, amph-ligand vaccines, antibody-functionalized thin films. - Dendritic cells (DCs): antigen presentation, MHC/peptide complexes, costimulatory molecules, lymph node homing via CCR7; “miniDC” and DC–cancer hybrid membranes. - Macrophages: tumor-homing, phagocytosis, M1/M2 polarization; CAR-M, iPSC-derived CAR-M, nanopackage-loaded macrophages. - NK cells: non-specific killing, CAR-NK, ErbB2-specific NK, micellar drug release at immune synapse. - Stem cells: MSCs, NSCs, iPSCs; tumor/inflammation tropism, regenerative potential. - Cancer cells: homologous targeting, tumor-associated antigens; engineered “killer” cancer cells, exosomal PD-L1 knockout. - Cell membranes: RBC, platelet, cancer cell, DC, macrophage, neutrophil, bacterial, hybrid membranes. - Extracellular vesicles (EVs): exosomes (30–150 nm), microparticles (100–1000 nm), M1 macrophage exosomes, 3D-MPs. - Subcellular organelles: mitochondria, endoplasmic reticulum membranes. - Bacteria: E. coli MG1655, E. coli Nissle 1917, engineered probiotics, outer membrane vesicles. Payloads / cargos: - Chemotherapeutics (DOX, PTX, oxaliplatin), immunomodulators (IL-2, IL-10, IL-15 superagonist, IFN-γ), checkpoint inhibitors (aPDL1, aPD1), adjuvants (CpG, R848, R837), antigens, siRNA, mRNA, CRISPR-Cas9 components, imaging agents, photosensitizers. Design principles: - Cell surface modification (adsorption, chemical conjugation, hydrophobic insertion, micro/nanomotors). - Cell conjugation (click chemistry, biotin–avidin). - Cell membrane wrapping (extrusion, sonication, hybrid membranes). - Genetic engineering (CRISPR-Cas9, gene editing, reprogramming). ---

Approach: Narrative review of preclinical and clinical literature. Model systems include: - In vitro: DC maturation, NK activation, T cell activation, macrophage polarization, antigen presentation. - In vivo: mouse models of melanoma, breast cancer, glioma, ovarian cancer, leukemia, colorectal cancer, rheumatoid arthritis, type 1 diabetes, sepsis, ischemic stroke, COVID-19. - Clinical trials: FDA-approved CAR-T products (Kymriah, Yescarta, Tecartus, Breyanzi), sipuleucel-T, iliadenec, CAR-M (CT-0508), NK cell therapies, MSC therapies, EV therapies, engineered bacteria. - Disease context: cancer, autoimmune diseases (RA, SLE, T1D), infectious diseases (COVID-19, sepsis), inflammatory diseases. ---

Key methods: Techniques and endpoints highlighted across cited studies: - Flow cytometry for immune cell subsets, DC maturation, M1/M2 polarization, NK activation. - ELISA for cytokines (IFN-γ, TNF-α, IL-2, IL-6, IL-1β). - Confocal/electron microscopy for membrane coating, cellular uptake, immune synapse formation. - In vivo tumor growth inhibition, survival analysis, metastasis assessment. - MRI, fluorescence imaging, PET for biodistribution and tracking. - Competitive binding assays for PD-1/PD-L1 blockade. - CRISPR-Cas9 gene editing for PD-L1 knockout, BCL11A enhancer editing. - Clinical response assessment: complete remission, overall response rate, survival. ---

Key results: - RBC hitchhiking: ~11.5% of drug-loaded nanoparticles carrying RBCs targeted the brain, 10× more efficient than traditional brain-targeting carriers. - Platelet-delivered aPDL1 (P-aPDL1): circulating half-life greatly increased vs free aPDL1; effectively prevented tumor recurrence and metastasis after surgery and prolonged survival in mice. - Neutrophil-carried PTX liposomes (PTX-CL/NEs): prolonged survival of glioma-bearing mice even with half the PTX dose; significantly inhibited postoperative glioma recurrence. - Neutrophil-mimicking nanoparticles: broad-spectrum neutralization of pro-inflammatory cytokines; prevented arthritis, decreased immune cell infiltration and edema, supported chondrocyte growth. - PIR@M nanoparticles: increased tumor M1 macrophage ratio from 11.27% to 29.44%; similar effect in spleen. - Clinical: Kymriah, Yescarta, Tecartus, Breyanzi FDA-approved; sipuleucel-T extends overall survival by 4.1 months; iliadenec + sunitinib doubled total remission rate vs sunitinib alone in metastatic RCC. ---

Interpretation: The authors claim that cell-based delivery systems have set off a revolution in clinical disease treatment by leveraging endogenous cells with minimized immunogenicity, expanding the therapeutic tool set and fundamentally changing drug delivery. They emphasize that multidisciplinary integration—chemistry, bioengineering, materials science, medicine—will overcome current bottlenecks such as limited infiltration, non-specific biodistribution, manufacturing, storage, and cost, enabling broader clinical application. ---

Limitations: - Safety: Overactivation of the immune system and cytokine release storm; autoimmune side effects; non-specific distribution causing toxicity to normal tissues; neurotoxicity in CAR-T therapy. - Insufficient infiltration: Some cells cannot cross physiological barriers or infiltrate tumor parenchyma effectively. - Manufacturing and storage: Facile preparation, scale-up manufacturing, long-term storage, and affordability remain challenging. - Cell engineering: Modifying cells without compromising critical functions is difficult; membrane extraction/purification may lose functionality. - Genetic engineering: Off-target risks, long-term side effects, ethical issues. - Tumor heterogeneity: Antigen escape and immune suppression limit efficacy. - Regulatory: Lack of clear regulations, policies, and safety evaluation guidelines for clinical translation. - As a review: Not a systematic review or meta-analysis; no primary data. This response is AI-generated, for reference only.