Modular nanotherapeutics with spatiotemporal precision for phase-specific treatment of intracerebral hemorrhage

Sep 29, 2026

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Intracerebral hemorrhage (ICH) is a life-threatening neurological disorder with spatiotemporally evolving pathological cascades, requiring interventions that dynamically match its multiphasic progression. This work reports modular PPP-based nanotherapeutics with sequential pharmacological actions for stage-specific therapy. The ROS-responsive PPP architecture enables programmed dissociation, on-demand anti-inflammatory release, and iron chelation, providing phase-precise hemostasis, inflammation attenuation, and ferroptosis suppression. In vitro and in vivo results show multimodal neuroprotection and reduced hematoma expansion, oxidative stress, and neuroinflammation.

LanguageEnglish

CategoryHealthcare

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Pages17

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Introduction

Intracerebral hemorrhage burden and evolving secondary injury

Limitations of surgery and current supportive pharmacology

Bioactive Materials 58 (2026) 331–347 Contents lists available at ScienceDirect Bioactive Materials journal [homepage:](homepage: www.keaipublishing.com/en/journals/bioactive-materials)[ www.keaipublishing.com/en/journals/bioactive-materials](homepage: www.keaipublishing.com/en/journals/bioactive-materials) | Modular nanotherapeutics with spatiotemporal precision for phase-specific treatment of intracerebral hemorrhage
Wanli Yu a,b,c,1 , Zhiyu Chend,1, Bo Wub,c, Chunfan Zhang e, Ying Han e, Dewei Zoub,c, Jianxiang Zhang d,e,f,g,* , Nan Wu a,b,c,**
a Chongqing School of University of Chinese Academy of Sciences (UCAS), Chongqing Medical University, Chongqing, 400016, China b Department of Neurosurgery, Chongqing General Hospital, School of Medicine, Chongqing University, Chongqing, 400014, China c Chongqing Key Laboratory of Neurodegenerative Diseases, Chongqing General Hospital, Chongqing University, Chongqing, 400014, China d Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
e Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing, 400038, China f Yu-Yue Pathology Scientific Research Center, 313 Gaoteng Avenue, Jiulongpo District, Chongqing, 400039, China
g State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, 400038, China | | | | | --- | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | | Keywords:
Intracerebral hemorrhage Oxidative stress Neuroinflammation Nanotherapy
Cell-free DNA Ferroptosis | | Intracerebral hemorrhage (ICH) is a life-threatening neurological disorder characterized by spatiotemporally evolving pathological cascades, necessitating interventions that dynamically adapt to its multiphasic injury progression. Here, we report modular polymer (PPP)-based nanotherapeutics engineered for stage-specific therapy of ICH through sequential pharmacological actions. The PPP architecture integrates a hydrophilic segment and a hydrophobic, reactive oxygen species (ROS)-responsive motif onto a polyamine scaffold, enabling ROS-triggered programmed dissociation, on-demand anti-inflammatory agent release, and iron chelation. This design confers spatiotemporal therapeutic precision: during the hyperacute phase, PPP nanoparticles promote rapid hemostasis and efficiently scavenge cell-free DNA (cfDNA); in the acute phase, they attenuate neuroinflammation through ROS-mediated hydrolysis and subsequent release of polyamine domains; and in the subacute phase, the exposed polyamines neutralize cytotoxic aldehydes and sequester iron ions to suppress ferroptosis. In vitro, PPPs demonstrated multimodal cytoprotection by attenuating oxidative stress and inflammation in microglial cells under hemin/cfDNA challenge, thereby preserving neuronal viability, and directly inhibiting neuronal ferroptosis via downregulating heme oxygenase-1 and activating glutathione peroxidase 4/ solute carrier family 7 member 11. In vivo, PPPs conferred comprehensive neuroprotection, significantly limiting hematoma expansion, reducing oxidative stress and neuroinflammation, and preventing iron-mediated neuronal death. By precisely interfacing with dynamic pathophysiology of ICH, this tunable nanotherapeutic platform represents a paradigm shift in targeted neurovascular injury management. | | 1. Introduction Intracerebral hemorrhage (ICH), the most devastating stroke subtype, occurs when cerebral vessels rupture and blood extravasates into the brain parenchyma. Affecting over 3.4 million individuals globally each year [1], ICH is most frequently associated with long-term disability and poor functional recovery [2–4]. The ICH pathology involves complex, evolving secondary injury cascades, yet no effective therapies exist to date. While surgical hematoma evacuation physically removes intraparenchymal clots, l

FAQs

What problem does the PPP-based nanotherapeutic platform target in intracerebral hemorrhage?

It targets the spatiotemporally evolving secondary injury cascades in ICH by delivering stage-specific therapy through sequential pharmacological actions.

How does the PPP design achieve phase-specific treatment?

The ROS-responsive PPP architecture enables ROS-triggered programmed dissociation, anti-inflammatory agent release, and iron chelation. This results in rapid hemostasis and cfDNA scavenging in the hyperacute phase, neuroinflammation attenuation in the acute phase, and ferroptosis suppression in the subacute phase.

What evidence supports therapeutic effects of PPPs in vitro and in vivo?

In vitro, PPPs protect microglial and neuronal viability by attenuating oxidative stress and inflammation and inhibiting neuronal ferroptosis. In vivo, PPPs provide comprehensive neuroprotection by limiting hematoma expansion, reducing oxidative stress and neuroinflammation, and preventing iron-mediated neuronal death.

Sep 29, 2026

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