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Neutrophil-based delivery platforms: from natural mechanisms to engineered therapeutics

Li, Yinggang, Zhang, Xue, Li, Yunkun, Sun, Ling, Hu, Na, Lui, Su, Duan, Zhenyu, Gong, Qiyong, Luo, Kui·2026·Theranostics
DOI 10.7150/thno.117363PMC PMC12665108
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Figure 1 Schematic illustration of targeted therapy at lesion sites via engineered neutrophils-mediated or neutrophil-mimicking drug delivery systems. Eight strategies have been developed for engineered neutrophil-mediated/mimetic drug delivery systems: in vitro neutrophil drug loading; in vivo neutrophil hitchhiking; genetic engineering of neutrophils; surface-engineering of neutrophils; neutrophil membrane-coated systems; hybrid membrane systems; neutrophil exosome systems; neutrophil-like cell systems. These systems have been demonstrated to enable precise delivery to inflammatory diseases, tumors, CNS pathologies, orthopedic disorders, and post-surgical sites.
Figure 1 Schematic illustration of targeted therapy at lesion sites via engineered neutrophils-mediated or neutrophil-mimicking drug delivery systems. Eight strategies have been developed for engineered neutrophil-mediated/mimetic drug delivery systems: in vitro neutrophil drug loading; in vivo neutrophil hitchhiking; genetic engineering of neutrophils; surface-engineering of neutrophils; neutrophil membrane-coated systems; hybrid membrane systems; neutrophil exosome systems; neutrophil-like cell systems. These systems have been demonstrated to enable precise delivery to inflammatory diseases, tumors, CNS pathologies, orthopedic disorders, and post-surgical sites.CC BY · PubMed Central
Figure 2 Physiological basis of neutrophils as a drug delivery system. Neutrophils originate and mature in the bone marrow before entering systemic circulation. Upon encountering inflammatory cues, they undergo a well-orchestrated sequence of migration steps—rolling, slow rolling, arrest, crawling, and diapedesis—to infiltrate affected tissues. Once activated, neutrophils can release therapeutics via detachment and NETs formation. Notably, phagocytosis during this process provides a physiological basis for drug loading and release.
Figure 2 Physiological basis of neutrophils as a drug delivery system. Neutrophils originate and mature in the bone marrow before entering systemic circulation. Upon encountering inflammatory cues, they undergo a well-orchestrated sequence of migration steps—rolling, slow rolling, arrest, crawling, and diapedesis—to infiltrate affected tissues. Once activated, neutrophils can release therapeutics via detachment and NETs formation. Notably, phagocytosis during this process provides a physiological basis for drug loading and release.CC BY · PubMed Central
Figure 3 Mechanisms of targeting distinct pathological sites by neutrophils. Neutrophils exhibit intrinsic targetability toward various pathological sites via different mechanisms, including targeting tumor sites, sterile acute inflammation sites, sterile chronic inflammation sites, and infection inflammation sites.
Figure 3 Mechanisms of targeting distinct pathological sites by neutrophils. Neutrophils exhibit intrinsic targetability toward various pathological sites via different mechanisms, including targeting tumor sites, sterile acute inflammation sites, sterile chronic inflammation sites, and infection inflammation sites.CC BY · PubMed Central
Figure 4 Neutrophil-based delivery strategies. Neutrophil-based delivery strategies include direct drug loading onto neutrophils ex vivo, in vivo hitchhiking, surface modification, and genetic engineering of neutrophils. In addition, NDDSs encompass neutrophil membrane-coated nanomedicines, hybrid membrane-coated nanomedicines, neutrophil-derived exosomes-coated nanomedicines, and neutrophil-mimicking nanoplatforms.
Figure 4 Neutrophil-based delivery strategies. Neutrophil-based delivery strategies include direct drug loading onto neutrophils ex vivo, in vivo hitchhiking, surface modification, and genetic engineering of neutrophils. In addition, NDDSs encompass neutrophil membrane-coated nanomedicines, hybrid membrane-coated nanomedicines, neutrophil-derived exosomes-coated nanomedicines, and neutrophil-mimicking nanoplatforms.CC BY · PubMed Central
Figure 5 The strategies for loading drugs into neutrophils include in vitro loading and in vivo hitchhiking. (A) Characterization and super-resolution imaging (SIM) of MTX-liposome-loaded neutrophils, confirming liposome localization on/in neutrophils. Scale bar: 5 µm. (B) Neutrophil-mediated delivery of liposomes to the ischemic heart post-IRI. Schematic of surgical procedure and injection of DiD-labeled liposome-loaded neutrophils, and in vivo fluorescence images of liposomes in the heart. Adapted with permission from 123, copyright 2020 Wiley-VCH GmbH. (C) Composition of ZGO@TiO₂@APL, and ultrasound-triggered drug release in GBM. Upon insolation, ROS generation facilitated the release of PTX for therapeutic action and anti-PD-1 for sustained tumor targeting. Adapted with permission from 134, copyright 2021 Wiley-VCH GmbH. (D) Schematic synthesis of NDDSs and in vivo fluorescence images of mice after intravenous injection of NDDSs in non-LPS-treated and LPS-treated 4T1 tumor-bearing mice. Adapted with permission from 135, copyright 2025 Wiley-VCH GmbH. (E) A neutrophil-hijacking nanoplatform for ischemic stroke therapy. (F) Light-sheet microscopy images for vascular distribution. Adapted with permission from 144, copyright 2025 Wiley-VCH GmbH. (G) Preparation of pathogen-mimicking nanoparticle via OMVs-coated NPs to retain PAMPs and TEM image of NPs@PBT (scale bar: 100 nm). (H) In vivo imaging of neutrophil infiltration in tumors pre- and post-PTT (left). Scale bar: 100 µm. Fluorescence-based in vivo imaging at different time points (right). Adapted with permission from 246, copyright 2020 Springer Nature.
Figure 5 The strategies for loading drugs into neutrophils include in vitro loading and in vivo hitchhiking. (A) Characterization and super-resolution imaging (SIM) of MTX-liposome-loaded neutrophils, confirming liposome localization on/in neutrophils. Scale bar: 5 µm. (B) Neutrophil-mediated delivery of liposomes to the ischemic heart post-IRI. Schematic of surgical procedure and injection of DiD-labeled liposome-loaded neutrophils, and in vivo fluorescence images of liposomes in the heart. Adapted with permission from 123, copyright 2020 Wiley-VCH GmbH. (C) Composition of ZGO@TiO₂@APL, and ultrasound-triggered drug release in GBM. Upon insolation, ROS generation facilitated the release of PTX for therapeutic action and anti-PD-1 for sustained tumor targeting. Adapted with permission from 134, copyright 2021 Wiley-VCH GmbH. (D) Schematic synthesis of NDDSs and in vivo fluorescence images of mice after intravenous injection of NDDSs in non-LPS-treated and LPS-treated 4T1 tumor-bearing mice. Adapted with permission from 135, copyright 2025 Wiley-VCH GmbH. (E) A neutrophil-hijacking nanoplatform for ischemic stroke therapy. (F) Light-sheet microscopy images for vascular distribution. Adapted with permission from 144, copyright 2025 Wiley-VCH GmbH. (G) Preparation of pathogen-mimicking nanoparticle via OMVs-coated NPs to retain PAMPs and TEM image of NPs@PBT (scale bar: 100 nm). (H) In vivo imaging of neutrophil infiltration in tumors pre- and post-PTT (left). Scale bar: 100 µm. Fluorescence-based in vivo imaging at different time points (right). Adapted with permission from 246, copyright 2020 Springer Nature.CC BY · PubMed Central
Figure 6 The strategies of surface modification and genetic engineering of neutrophils. (A) Schematic of NEs@STING-Mal-NP preparation via reduction-click chemistry. Confocal images confirmed that STING-Mal-NP-RhoB (red) bound to neutrophils with or without tris (2-carboxyethyl) phosphine treatment. Nuclei stained with Hoechst (blue). Scale bar: 5 μm. Adapted with permission from 69, copyright 2023 American Chemical Society. (B) Preparation of NE/CAMPs by incubating anti-CD11b-Fab-conjugated CAMPs with primary NEs. Confocal images supported NEs with surface-bound CAMPs. (C) Biodistribution of NE/CAMPs in orthotopic GL261 glioma mice at 24 h post-injection. Images from an in vivo imaging system confirmed increased brain accumulation of NE/CAMPs versus the control NEs. Adapted with permission from 26, copyright 2024 John Wiley and Sons. (D) CAR-engineered hPSC-derived neutrophils loaded with a hypoxia-targeting drug (tirapazamine) via rough SiO₂ (R-SiO₂) NPs for dual immunochemotherapy. (E) Polarized F-actin accumulates at the interface between CAR-neutrophils and tumor cells, followed by the release of R-SiO₂-tirapazamine nanoparticles upon phagocytosis, which are subsequently internalized by the tumor cells. Adapted with permission from 28, copyright 2023 Springer Nature.
Figure 6 The strategies of surface modification and genetic engineering of neutrophils. (A) Schematic of NEs@STING-Mal-NP preparation via reduction-click chemistry. Confocal images confirmed that STING-Mal-NP-RhoB (red) bound to neutrophils with or without tris (2-carboxyethyl) phosphine treatment. Nuclei stained with Hoechst (blue). Scale bar: 5 μm. Adapted with permission from 69, copyright 2023 American Chemical Society. (B) Preparation of NE/CAMPs by incubating anti-CD11b-Fab-conjugated CAMPs with primary NEs. Confocal images supported NEs with surface-bound CAMPs. (C) Biodistribution of NE/CAMPs in orthotopic GL261 glioma mice at 24 h post-injection. Images from an in vivo imaging system confirmed increased brain accumulation of NE/CAMPs versus the control NEs. Adapted with permission from 26, copyright 2024 John Wiley and Sons. (D) CAR-engineered hPSC-derived neutrophils loaded with a hypoxia-targeting drug (tirapazamine) via rough SiO₂ (R-SiO₂) NPs for dual immunochemotherapy. (E) Polarized F-actin accumulates at the interface between CAR-neutrophils and tumor cells, followed by the release of R-SiO₂-tirapazamine nanoparticles upon phagocytosis, which are subsequently internalized by the tumor cells. Adapted with permission from 28, copyright 2023 Springer Nature.CC BY · PubMed Central
Figure 7 Biomimicking drug delivery systems prepared by coating NPs with neutrophil membranes, hybrid membranes from neutrophils and other cell types. (A) Schematic illustration of FKPN nanodevice preparation. Adapted with permission from 168, copyright 2023 Springer Nature. (B) Schematic of activated neutrophil membrane-coated NPs and their assembly. Adapted with permission from 165, copyright 2024 American Chemical Society. (C) Schematic diagram for the preparation of MnPM via fusion of neutrophil and macrophage cell membranes. Adapted with permission from 177, copyright 2024 Springer Nature. (D) The preparation process of NED@MnO₂-DOX NPs with a schematic structure and their TEM image. Adapted with permission from 179, copyright 2024 American Chemical Society.
Figure 7 Biomimicking drug delivery systems prepared by coating NPs with neutrophil membranes, hybrid membranes from neutrophils and other cell types. (A) Schematic illustration of FKPN nanodevice preparation. Adapted with permission from 168, copyright 2023 Springer Nature. (B) Schematic of activated neutrophil membrane-coated NPs and their assembly. Adapted with permission from 165, copyright 2024 American Chemical Society. (C) Schematic diagram for the preparation of MnPM via fusion of neutrophil and macrophage cell membranes. Adapted with permission from 177, copyright 2024 Springer Nature. (D) The preparation process of NED@MnO₂-DOX NPs with a schematic structure and their TEM image. Adapted with permission from 179, copyright 2024 American Chemical Society.CC BY · PubMed Central
Figure 8 Representative strategies for transporting drugs by neutrophil-derived exosomes. (A) Steps for the isolation of exosomes from peripheral blood neutrophils (PBNs). (B) TEM images of neutrophil-derived exosomes. Scale bar: 100 nm. Adapted with permission from 189, copyright 2022 The American Association for the Advancement of Science. (C) The preparation of activated neutrophil exosome mimetics (aPMNEMs) via multilayer filtration of LPS-stimulated neutrophils. (D) TEM characterization of native and activated neutrophil-derived exosomes. PMNExo: Polymorphonuclear neutrophil-derived exosomes; aPMNExo: activated neutrophil-derived exosomes; PMNEM: neutrophil exosome mimetics; and aPMNEM: activated neutrophil exosome mimetics. Adapted with permission from 190, copyright 2023 Springer Nature.
Figure 8 Representative strategies for transporting drugs by neutrophil-derived exosomes. (A) Steps for the isolation of exosomes from peripheral blood neutrophils (PBNs). (B) TEM images of neutrophil-derived exosomes. Scale bar: 100 nm. Adapted with permission from 189, copyright 2022 The American Association for the Advancement of Science. (C) The preparation of activated neutrophil exosome mimetics (aPMNEMs) via multilayer filtration of LPS-stimulated neutrophils. (D) TEM characterization of native and activated neutrophil-derived exosomes. PMNExo: Polymorphonuclear neutrophil-derived exosomes; aPMNExo: activated neutrophil-derived exosomes; PMNEM: neutrophil exosome mimetics; and aPMNEM: activated neutrophil exosome mimetics. Adapted with permission from 190, copyright 2023 Springer Nature.CC BY · PubMed Central
Figure 9 Strategies of using neutrophil-like cells for targeted drug delivery. (A) Design and fabrication of RvD2-loaded nanovesicles to target inflammatory brain endothelium during post-stroke reperfusion. (B) The RvD2-loaded nanovesicles reduced neutrophil infiltration in the middle cerebral artery occlusion mouse model, confirmed by intravital 3D microscopy. Scale bar: 20 μm. Adapted with permission from 197, copyright 2019 American Chemical Society. (C) Schematic illustration of the preparation process for LNP-N@HMVs, a hybrid membrane-coated antibiotic delivery system. (D) Confocal images of E. coli biofilms treated with various formulations at an equivalent norfloxacin concentration after live/dead staining. Adapted with permission from 199, copyright 2024 The American Association for the Advancement of Science.
Figure 9 Strategies of using neutrophil-like cells for targeted drug delivery. (A) Design and fabrication of RvD2-loaded nanovesicles to target inflammatory brain endothelium during post-stroke reperfusion. (B) The RvD2-loaded nanovesicles reduced neutrophil infiltration in the middle cerebral artery occlusion mouse model, confirmed by intravital 3D microscopy. Scale bar: 20 μm. Adapted with permission from 197, copyright 2019 American Chemical Society. (C) Schematic illustration of the preparation process for LNP-N@HMVs, a hybrid membrane-coated antibiotic delivery system. (D) Confocal images of E. coli biofilms treated with various formulations at an equivalent norfloxacin concentration after live/dead staining. Adapted with permission from 199, copyright 2024 The American Association for the Advancement of Science.CC BY · PubMed Central
Figure 10 Challenges and future perspectives of NDDSs. NDDSs or neutrophil-derived biomimetic drug delivery systems face major challenges, including (1) unintended side effects after the activation of neutrophils; (2) product inconsistency due to the inherent heterogeneity of neutrophil-derived components; and (3) time-consuming and costly development of these drug delivery systems. To address these issues, future strategies can leverage artificial intelligence to optimize discovery and design of these drug delivery systems, employ microfluidic and 3D printing technologies to improve and standardize manufacturing processes, discover novel targeting mechanisms of neutrophils, control drug loading and release processes from NDDSs, and unveil the interplay between neutrophils and the microbiota.
Figure 10 Challenges and future perspectives of NDDSs. NDDSs or neutrophil-derived biomimetic drug delivery systems face major challenges, including (1) unintended side effects after the activation of neutrophils; (2) product inconsistency due to the inherent heterogeneity of neutrophil-derived components; and (3) time-consuming and costly development of these drug delivery systems. To address these issues, future strategies can leverage artificial intelligence to optimize discovery and design of these drug delivery systems, employ microfluidic and 3D printing technologies to improve and standardize manufacturing processes, discover novel targeting mechanisms of neutrophils, control drug loading and release processes from NDDSs, and unveil the interplay between neutrophils and the microbiota.CC BY · PubMed Central

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Metadata

Authors
Li, Y., Zhang, X., Li, Y., Sun, L., Hu, N., Lui, S., Duan, Z., Gong, Q., & Luo, K.
Venue
Theranostics
Publisher
Ivyspring International Publisher
Published
2026-01-01
Volume
16
Issue
1
Pages
123-155
ISSN
1838-7640
DOI
10.7150/thno.117363
PMC
PMC12665108
Cited by
42
References
0
Language
en

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