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Injectable hybrid hydrogels enhance macrophage communication via second messenger amplification.

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Title: Injectable hybrid hydrogels enhance macrophage communication via second messenger amplification.
Authors: Du, Yawei1,2 (AUTHOR), Huang, Fanyi1,3 (AUTHOR), Chen, Hui1,4 (AUTHOR), Ling, Shifeng1 (AUTHOR), Wang, Haoran1 (AUTHOR), Zhuang, Yaping1 (AUTHOR), Wu, Tianqi5 (AUTHOR), Yang, Ke3 (AUTHOR), Jin, Wei1,3 (AUTHOR) jinwei@shsmu.edu.cn, Cui, Wenguo1,2 (AUTHOR) wgcui@sjtu.edu.cn
Source: Journal of Controlled Release. Mar2026, Vol. 391, pN.PAG-N.PAG. 1p.
Subjects: Macrophage activation, Hydrogels, Biomimetic polymers, Adenosine monophosphate, Cell communication, Phagocytosis, Cardiac regeneration
Abstract: Macrophages play a pivotal role in tissue regeneration and immune regulation through efferocytosis and other mechanisms, with their intracellular communication largely dependent on second messengers (e.g. , cyclic adenosine monophosphate, cAMP). However, the broad-spectrum nature of these second messengers renders related interventions susceptible to uncontrollable systemic and off-target effects. Here, we developed an injectable apoptosis-mimicking hybrid hydrogel (PAS@Gel) that enables specific and coordinated macrophage intervention of both first and second messengers involved in efferocytosis, thereby optimizing macrophage communication and promoting tissue regeneration. First, the hybrid hydrogel forms an ECM-mimicking 3D structure through a thermosensitive copolymer and incorporates apoptosis-mimicking vesicles (PAS), enabling the first messenger regulation of macrophage efferocytosis Find-me/Eat-me processes specifically. Subsequently, Rolipram delivered by PAS inhibits cAMP phosphodiesterase (PDE4), synergistically enhancing the second messenger-mediated pathway to amplify intracellular signaling. In vitro experiments demonstrated that PAS@Gel synergistically activates macrophage Tyro3-Axl-Mer receptors, RAC1, and cAMP-related signaling pathways, significantly enhancing efferocytosis-related macrophage communication. In vivo studies using a myocardial ischemia/reperfusion (MI/R) injury model further confirmed that in-situ injection of PAS@Gel effectively alleviated inflammation via second messenger amplification, and significantly promoted myocardial tissue repair. This study presents a novel strategy for guiding tissue regeneration by enhancing macrophage second messenger regulation. Macrophages play a pivotal role in tissue regeneration through efferocytosis and other mechanisms. This study introduces injectable hybrid hydrogels that enhances macrophage communication via a second messenger amplification. [Display omitted] [ABSTRACT FROM AUTHOR]
Copyright of Journal of Controlled Release is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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Header DbId: egs
DbLabel: Engineering Source
An: 192082777
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: Injectable hybrid hydrogels enhance macrophage communication via second messenger amplification.
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  Label: Authors
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  Data: <searchLink fieldCode="AR" term="%22Du%2C+Yawei%22">Du, Yawei</searchLink><relatesTo>1,2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Huang%2C+Fanyi%22">Huang, Fanyi</searchLink><relatesTo>1,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chen%2C+Hui%22">Chen, Hui</searchLink><relatesTo>1,4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ling%2C+Shifeng%22">Ling, Shifeng</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wang%2C+Haoran%22">Wang, Haoran</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhuang%2C+Yaping%22">Zhuang, Yaping</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wu%2C+Tianqi%22">Wu, Tianqi</searchLink><relatesTo>5</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yang%2C+Ke%22">Yang, Ke</searchLink><relatesTo>3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Jin%2C+Wei%22">Jin, Wei</searchLink><relatesTo>1,3</relatesTo> (AUTHOR)<i> jinwei@shsmu.edu.cn</i><br /><searchLink fieldCode="AR" term="%22Cui%2C+Wenguo%22">Cui, Wenguo</searchLink><relatesTo>1,2</relatesTo> (AUTHOR)<i> wgcui@sjtu.edu.cn</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Controlled+Release%22">Journal of Controlled Release</searchLink>. Mar2026, Vol. 391, pN.PAG-N.PAG. 1p.
– Name: Subject
  Label: Subjects
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  Data: <searchLink fieldCode="DE" term="%22Macrophage+activation%22">Macrophage activation</searchLink><br /><searchLink fieldCode="DE" term="%22Hydrogels%22">Hydrogels</searchLink><br /><searchLink fieldCode="DE" term="%22Biomimetic+polymers%22">Biomimetic polymers</searchLink><br /><searchLink fieldCode="DE" term="%22Adenosine+monophosphate%22">Adenosine monophosphate</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+communication%22">Cell communication</searchLink><br /><searchLink fieldCode="DE" term="%22Phagocytosis%22">Phagocytosis</searchLink><br /><searchLink fieldCode="DE" term="%22Cardiac+regeneration%22">Cardiac regeneration</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Macrophages play a pivotal role in tissue regeneration and immune regulation through efferocytosis and other mechanisms, with their intracellular communication largely dependent on second messengers (e.g. , cyclic adenosine monophosphate, cAMP). However, the broad-spectrum nature of these second messengers renders related interventions susceptible to uncontrollable systemic and off-target effects. Here, we developed an injectable apoptosis-mimicking hybrid hydrogel (PAS@Gel) that enables specific and coordinated macrophage intervention of both first and second messengers involved in efferocytosis, thereby optimizing macrophage communication and promoting tissue regeneration. First, the hybrid hydrogel forms an ECM-mimicking 3D structure through a thermosensitive copolymer and incorporates apoptosis-mimicking vesicles (PAS), enabling the first messenger regulation of macrophage efferocytosis Find-me/Eat-me processes specifically. Subsequently, Rolipram delivered by PAS inhibits cAMP phosphodiesterase (PDE4), synergistically enhancing the second messenger-mediated pathway to amplify intracellular signaling. In vitro experiments demonstrated that PAS@Gel synergistically activates macrophage Tyro3-Axl-Mer receptors, RAC1, and cAMP-related signaling pathways, significantly enhancing efferocytosis-related macrophage communication. In vivo studies using a myocardial ischemia/reperfusion (MI/R) injury model further confirmed that in-situ injection of PAS@Gel effectively alleviated inflammation via second messenger amplification, and significantly promoted myocardial tissue repair. This study presents a novel strategy for guiding tissue regeneration by enhancing macrophage second messenger regulation. Macrophages play a pivotal role in tissue regeneration through efferocytosis and other mechanisms. This study introduces injectable hybrid hydrogels that enhances macrophage communication via a second messenger amplification. [Display omitted] [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Controlled Release is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1016/j.jconrel.2026.114610
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 1
        StartPage: N.PAG
    Subjects:
      – SubjectFull: Macrophage activation
        Type: general
      – SubjectFull: Hydrogels
        Type: general
      – SubjectFull: Biomimetic polymers
        Type: general
      – SubjectFull: Adenosine monophosphate
        Type: general
      – SubjectFull: Cell communication
        Type: general
      – SubjectFull: Phagocytosis
        Type: general
      – SubjectFull: Cardiac regeneration
        Type: general
    Titles:
      – TitleFull: Injectable hybrid hydrogels enhance macrophage communication via second messenger amplification.
        Type: main
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            NameFull: Du, Yawei
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            NameFull: Huang, Fanyi
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            NameFull: Chen, Hui
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            NameFull: Ling, Shifeng
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            NameFull: Wang, Haoran
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            NameFull: Zhuang, Yaping
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            NameFull: Yang, Ke
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            NameFull: Jin, Wei
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            – D: 10
              M: 03
              Text: Mar2026
              Type: published
              Y: 2026
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              Value: 391
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            – TitleFull: Journal of Controlled Release
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