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

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.