Modular assembled biomimetic nanobubbles for synergistic therapy of ischemic stroke via cascade modulation thrombo-inflammatory network.

Dynamic pathology-adaptive nanodelivery systems represent a promising frontier in acute ischemic stroke (AIS) therapy. Here, we report a thrombo-inflammatory cascade-targeted biomimetic nanobubble engineered through gas-liquid interfacial modular assembly of platelet membranes and immunomodulator fingolimod (FTY720). Molecular dynamics simulations uncovered a gas-liquid interfacial self-organization mechanism driving the ordered spatial distribution of platelet membrane lipid rafts and amphiphilic FTY720 to fabricate platelet membrane coated FTY720 nanobubble (PFNB). Such modular assembled PFNBs can promote the effective presentation of targeted proteins and drug molecular functions on the biointerface, enabling precise sequential lesion targeting, enhanced blood-brain barrier penetration and inflammatory microglial uptake, significantly improving drug delivery efficiency. Therapeutic efficacy analysis via whole-genome RNA sequencing demonstrated a virtuous cycle between anti-inflammatory regulation and vascular protection, ultimately mitigating the brain tissue damage. Therefore, PFNBs provide a paradigm for the modular construction and biointerface efficacy regulation of multifunctional integrated biomimetic nano-delivery systems, offering promising strategies for multi-target synergistic treatment of AIS.