Convergence of nanomedicine and neutrophils for drug delivery

Abstract

Neutrophils have recently emerged as promising carriers for drug delivery due to their unique properties including rapid response toward inflammation, chemotaxis, and transmigration. When integrated with nanotechnology that has enormous advantages in improving treatment efficacy and reducing side effects, neutrophil-based nano-drug delivery systems have expanded the repertoire of nanoparticles employed in precise therapeutic interventions by either coating nanoparticles with their membranes, loading nanoparticles inside living cells, or engineering chimeric antigen receptor (CAR)-neutrophils. These neutrophil-inspired therapies have shown superior biocompatibility, targeting ability, and therapeutic robustness. In this review, we summarized the benefits of combining neutrophils and nanotechnologies, the design principles and underlying mechanisms, and various applications in disease treatments. The challenges and prospects for neutrophil-based drug delivery systems were also discussed.

Keywords: Cell therapy; Drug delivery; Nanotechnology; Neutrophil.

Graphical abstract

Fig. 1

Schematic illustration of the design principles of combining neutrophils and nanomedicine for applications in various diseases.

Fig. 2

Neutrophil membrane-coated nanoparticles. a) Schematic illustration of enhanced inflamed joint accumulation of neutrophil membrane coated Poly (lactic-co-glycolic acid) (PLGA) nanoparticles for synovial inflammation inhibition. Reproduced with permission [27]. Copyright 2018, Springer Nature. b) Schematic illustration of neutrophils activation, membrane isolation, and extrusion for generating neutrophils-simulated liposomes. Reproduced with permission [28]. Copyright 2019, Elsevier B.V.

Fig. 3

Versatile mechanisms of loading nanoparticles into living neutrophils. a) The internalization of Paclitaxel (PTX)-loaded liposomes and inflammatory site-specific release for postoperative malignant glioma. Reproduced with permission [30]. Copyright 2017, Springer Nature. b) Receptor-mediated phagocytosis for loading into neutrophils. Reproduced with permission [44]. Copyright 2022, Royal Society of Chemistry. c) Rough mesoporous SiO₂ nanoparticles phagocytosed into neutrophils achieved 95 % loading efficiency. Reproduced with permission [45]. Copyright 2023, Springer Nature. d) Conjugation of nanoparticles on neutrophil surface through electrostatic attraction. Reproduced with permission [46]. Copyright 2021, Royal Society of Chemistry. e) Peptide-anchored nanoparticles on the membrane of neutrophils. Reproduced with permission [47]. Copyright 2023, Elsevier B.V.

Fig. 4

Taking advantages of neutrophils to cross the blood-brain barrier for brain diseases. a) The extent of nanoparticles endocytosed within neutrophils over time after injection. Reproduced with permission [58]. Copyright 2017, Ivyspring International Publisher. b) Fluorescence imaging of mice after delivering by neutrophils to the ischemic brain. Reproduced with permission [54]. Copyright 2019, American Association for the Advancement of Science. c) Images of brain coronal sections in sham-operated mice and stroke mice indicating inflammation recruited neutrophil membrane-coating nano-enzyme. Reproduced with permission [80]. Copyright 2021, American Chemical Society.

Fig. 5

Applications of combining neutrophils and nanoparticles for cancer treatment. a) Treatment efficacy of PTX-loaded liposomes delivered by neutrophils for glioma. Reproduced with permission [30]. Copyright 2017, Springer Nature. b) Superior glioma tumor-targeting ability of DiR-labeled neutrophil exosomes in vivo. Reproduced with permission [42]. Copyright 2021, Elsevier Ltd. c) Neutrophil membrane serves as sponge to absorb cytokines for controlling malignant tumors. Reproduced with permission [87]. Copyright 2023, Acta Materialia Inc. d) The apoptosis and NETs of neutrophils induced by inflammatory signals in the tumor microenvironment for loaded-contents release. Reproduced with permission [61]. Copyright 2022, Elsevier B.V.

Fig. 6

Enhancing targeting capability for tumor therapy. a) Dual neutrophil-macrophage membrane coating of nanoparticles for complementary targeting. Reproduced with permission [83]. Copyright 2021, Elsevier B.V. b) Using CXCL1 chemokine-laden polymer hydrogels for attracting neutrophils. Reproduced with permission [51]. Copyright 2019. c) Targeting macrophages in rheumatoid arthritis by peptide anchoring and neutrophil membrane coating. Reproduced with permission [102]. Copyright 2023, Springer Nature. d) Inflammatory signals induced by photodynamic therapy for amplification and accumulation of photoactive neutrophil in tumor. Reproduced with permission [93]. Copyright 2021, Elsevier Ltd.

Fig. 7

Engineered CAR-neutrophils for nanodrug delivery. Reproduced with permission [45]. Copyright 2023, Springer Nature.

Fig. 8

Engineering neutrophils and other applications. a) The imaging of O₂ radical dots for colorectal cancer peritoneal metastasis and ear swelling with in-situ assistance of neutrophils. Reproduced with permission [47]. Copyright 2023, Elsevier B.V. b) Ru complex coated by neutrophil membrane for early diagnosis of osteoarthritis. Reproduced with permission [31]. Copyright 2022, Royal Society of Chemistry.