- G5.N(Gly)OH-PBA dendrimer co-loaded with fibronectin and edaravone forms 122.2 nm GOPFE nanocomplexes with colloidal stability and pH/ROS dual-sensitive release.
- FN-mediated recognition and abundant dendrimer hydroxyl termini enable BBB crossing, selective accumulation in cerebral inflammatory lesions and efficient uptake by microglia and neurons.
- GOPFE suppresses ROS overproduction, attenuates neuroinflammation and neuronal apoptosis, promotes angiogenesis, reduces infarct volume and improves neurological recovery with favourable biosafety.
Acta Biomater. 2026 Aug 11:S1742-7061(26)00549-0. doi: 10.1016/j.actbio.2026.08.016. Online ahead of print.
ABSTRACT
Development of nanomedicines that can cross blood-brain barrier (BBB) for effective multi-target mitigation of ischemic stroke (IS) is still challenging. Here, we report a hydroxylated poly(amidoamine) dendrimer-based delivery system co-loaded with the immunomodulator fibronectin (FN) protein and the antioxidant neuroprotective drug edaravone (EDV) to tackle IS. We show that generation 5 (G5) poly(amidoamine) dendrimers partially functionalized with phenylboronic acid (PBA) and fully terminated with glycidol hydroxyl groups are able to co-load FN/EDV to form G5.N(Gly)OH-PBA/FN/EDV (GOPFE) nanocomplexes (NCs). The GOPFE exhibits a uniform particle size of 122.2 nm, satisfactory colloidal stability, pH/reactive oxygen species (ROS) dual-sensitive drug release behavior and favorable cytocompatibility. Benefiting from FN-mediated active targeting, the GOPFE can be efficiently internalized by microglia and neuronal cells and can cross BBB to selectively accumulate in cerebral inflammatory lesion due to the abundant dendrimer terminal hydroxyl groups and the FN-derived targeting capability. Mechanistically, the GOPFE effectively suppresses oxygen-glucose deprivation-triggered ROS overproduction, restrains excessive neuroinflammation, and ultimately alleviates neuronal apoptosis. In an IS rat model, the GOPFE preferentially accumulates in ischemic lesion, markedly reduces cerebral infarct volume, facilitates neurological functional recovery, and ameliorates ischemic BBB damage via FN-mediated angiogenesis effect. Moreover, the GOPFE orchestrates inflammatory and immune homeostasis, mitigates neuroinflammatory cascades, and attenuates neuronal damage, thereby executing comprehensive multi-target neuroprotection. Hence, the developed GOPFE NCs may hold a great promise as a targeted therapeutic nanomedicine for IS and other inflammation-related cerebrovascular diseases. STATEMENT OF SIGNIFICANCE: Development of blood-brain barrier (BBB)-crossing nanomedicines for effective multi-target mitigation of ischemic stroke (IS) is still challenging. Herein, we design a hydroxylated phenylboronic acid (PBA)-functionalized PAMAM dendrimer of G5.N(Gly)OH-PBA (GOP) to co-load fibronectin (FN) and edaravone (EDV) for neuroprotection by reducing oxidative stress and modulating the inflammatory microenvironment in IS. The obtained G5.N(Gly)OH-PBA/FN/EDV (GOPFE) nanocomplexes can cross BBB to target inflammatory lesions due to the dendrimer surface hydroxyl groups and FN-mediated recognition. In the tMCAO/R rat model of IS, GOPFE presents desired biosafety and potent synergistic therapeutic efficacy of FN and EDV to markedly reduce cerebral infarct volume, relieve oxidative stress, rescue neurons from apoptosis, promote cerebral angiogenesis, and alleviate excessive neuroinflammation for high-efficiency synergistic therapy of IS.
PMID:42580614 | DOI:10.1016/j.actbio.2026.08.016
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