Recent progress in targeted delivery vectors based on biomimetic nanoparticles

Purpose: Synthetic nanoparticles face physiological barriers, RES clearance, and unintended biological interactions despite PEGylation and ligand grafting. Biological vectors—cell membranes, extracellular vesicles (EVs), and viruses—offer biocompatibility, biodegradability, immune evasion, and natural targeting. This review summarizes BNPs integrating biological vectors with functional agents for targeted delivery in imaging and therapy.

Hypothesis: No formal experimental hypothesis. Central thesis: biomimetic nanoparticles (BNPs) constructed by camouflaging synthetic nanoparticles with cell membranes, EVs (exosomes and microvesicles), or viral nanoparticles can inherit natural targeting, immune evasion, and long circulation properties, and with deliberate modification achieve multi-functional, precise targeted delivery of contrast agents, chemotherapy drugs, nucleic acids, and genes for refractory disease therapy.

Aims: Summarize recent advances in targeted delivery vectors based on cell membranes, EVs, and viruses. - Highlight construction methods and targeting strategies (passive, homologous, active, stimuli-responsive). - Review applications of BNPs in biomedical imaging and therapy, particularly for cancer. - Discuss clinical translation landscape, challenges, and future exploitation trends.

Delivery system: Cell membrane vectors: red blood cell membrane (RBCM), cancer cell membrane (CCM), immune cell membranes (neutrophil, NK, macrophage), platelet membrane, MDSC membrane, hybrid membranes (RBC–platelet, RBC–cancer cell, cancer–macrophage–platelet). - EV vectors: exosomes (40–100 nm), microvesicles (50–1000 nm), apoptotic bodies (1–5 μm), ARMMs, RBC-derived MVs, tumor cell-derived MVs. - Viral nanoparticles (VNPs): mammalian viruses (SV40, vaccinia, hepatitis B core, AAV, lentivirus, adenovirus, rabies virus glycoprotein, FMD VNPs, polyomavirus), bacteriophages (Qβ, P22, MS2, filamentous phage), plant viruses (tobacco mosaic virus, cowpea mosaic virus, cowpea chlorotic mottle virus, Physalis mottle virus). - Core materials: PLGA, MSNs, gold nanoparticles/nanostars/nanocages, iron oxide/magnetic nanoclusters, black phosphorus quantum dots, UCNPs, RENPs, melanin, copper sulfide, nanogels, liposomes, polymeric micelles, dendrimers. - Payloads: doxorubicin, paclitaxel, cisplatin/phenanthriplatin, methotrexate, gemcitabine, rapamycin, carfilzomib, siRNA, mRNA, miRNA, CRISPR-Cas9/sgRNA, contrast agents (ICG, Gd, Dy, Cy5, Cy7.5, QDs), photosensitizers (Ce6, TCPP, PpIX), immunoadjuvants (CpG, MPLA, R837, imiquimod), antibodies (anti-PD-L1, anti-IL-1β), vaccines. - Targeting/functionalization: RGD/cRGD, TAT, iRGD, folate, transferrin, mannose, anti-EGFR, anti-HER2, anti-CD205, RVG peptide, CP05 anchor peptide, DGEA, VCAM-1/S100A9 targeting peptides, magnetic guidance, pH/enzyme/redox/NIR-responsive release.

Approach: Comprehensive review of preclinical and clinical literature; no primary experiments. In vitro systems include MDA-MB-435/231, MCF-7, U87 MG, HeLa, HepG2, B16F10, 4T1, PC-3, SK-BR-3, A549, and RAW264.7 cells, among others. In vivo models include BALB/c nude mice, C57BL/6 mice, ApoE⁻/⁻ mice, orthotopic glioma, melanoma, breast cancer, HCC, prostate cancer, atherosclerosis, myocardial infarction, and brain disease models. Clinical trials cover EVs (NCT01294072, NCT01159288, NCT03384433, NCT03608631, NCT04592484), MVs (NCT01854866, NCT02657460, ChiCTR-ICR-15006304, ChiCTR-OIB-15007589), and viral vectors (Luxturna, Zolgensma, AAV, retrovirus, adenovirus trials).

Key methods: Nanoparticle/vector characterization: size, zeta potential, morphology (TEM), membrane protein retention (SDS-PAGE, Western blot, proteomics). - Cellular uptake and internalization: flow cytometry, confocal microscopy, homotypic targeting assays. - Immune response: DC maturation, CD4⁺/CD8⁺ T cell populations, cytokine secretion (IFN-γ), tetramer staining. - In vivo imaging: NIR fluorescence, upconversion luminescence (UCL), MRI, CT, photoacoustic, two-photon imaging. - Therapeutic efficacy: tumor growth inhibition, metastasis inhibition, survival, gene silencing (GFP knockdown), genome editing. - Clinical endpoints: safety, tolerability, pharmacokinetics, pharmacodynamics, adverse events.

Key results: RBCM-coated PLGA nanoparticles improved half-life by ~50% vs PEGylated nanoparticles and were detected in circulation after 72 h. - NM-NP-CFZ (neutrophil membrane-coated carfilzomib PLGA NPs) reduced lung metastasis by 87.2% and decreased S100A9 expression by 71% vs 44% (NP-CFZ) and 41% (free CFZ). - Dox@NKsomes increased tumor inhibition rate by 14.81% versus bulk doxorubicin. - MM-UCNPs showed excellent cancer-targeting and biocompatibility in MCF-7 breast tumor xenografts. - DCuS@RBC-B16 NPs achieved complete melanoma suppression under 1064 nm NIR laser via synergistic PTT and chemotherapy. - Melanin@RBC-M with 1:1 membrane ratio showed superior targeted delivery and PTT effect vs bulk melanin or other ratios. - EMPCs (tumor-derived exosome-coated prodrug NPs) inhibited focal metastasis via CTC elimination and FAK/MMP pathway mediation. - Exo-CP05 with M12 peptide increased dystrophin protein expression 18-fold in quadriceps of mdx mice vs CP05-PMO. - siRNA@TMV-TAT knocked down GFP-positive cells to much lower levels in ESCs/GFP and in MHCC97-H/GFP tumors. - PhenPt-TMV showed smaller tumors and longer survival than PhenPt, cisplatin, or TMV in MDA-MB-231 xenografts. - Clinical: cisplatin-loaded MVs killed >95% cancer cells in malignant fluids of advanced lung cancer patients; MVs@MTX showed targeting and immunosuppression without adverse side effects in 11 end-stage lung cancer patients with MPE.

Interpretation: BNPs based on cell membranes, EVs, and viruses integrate natural targeting, immune evasion, and long circulation with synthetic nanoparticle versatility, enabling potent therapy against refractory diseases, especially cancers. However, clinical translation requires full investigation of toxicity, biodistribution, and immunology. Continued study of BNP biology and understanding of therapeutic challenges will lay the foundation for future clinical success.

Limitations: Review article; no primary data. - Stability issues: size, shape, and components vary by source and modification; vectors are difficult to preserve and easily deactivated. - Large-scale production challenges: immature isolation/purification, low yields, improper modification, insufficient loading/delivery efficiency; purification methods can affect quality and quantity. - Safety and effectiveness unclear in humans: no standard evaluation criteria analogous to Lipinski's Rule of Five for BNPs; carcinogenic risk if nuclear/genetic material is not fully removed from cancer cell membranes. - Excessive immune cell membrane coating may trigger inflammation. - Viral vectors may integrate genome materials or induce immune responses; repeated application problematic. - EVs have low loading efficiency due to nanoscale size; heterogeneity in size and molecular constitution. - Most studies remain in laboratory stage; few clinical trials, mostly early phase. - Protein corona can mask targeting ligands. - Tumor heterogeneity, extracellular matrix barriers, and inter-patient variability complicate universal design.