Dual-stiffness nanoparticles for compartment-specific drug delivery in stroke

Abstract Ischemic stroke presents a dual therapeutic challenge, involving dynamic and compartmentalized pathology in both the peripheral immune system and the central nervous system. Departing from conventional holistic treatment strategies, we developed a spatially tiered drug delivery approach using a combination of dual-stiffness nanoparticles (NPs) for compartment-specific therapy. Exploiting stiffness-dependent biodistribution, stiff NPs preferentially targeted peripheral immune cells, delivering anti-inflammatory agents to attenuate systemic inflammation and prevent immune cell infiltration into the brain. In parallel, soft NPs, shielded from immune uptake, efficiently penetrated the brain to deliver neuroprotectants and restore the damaged neural microenvironment. Mechanistic studies indicate that this selective distribution arises from the interplay between NP stiffness-dependent membrane energetics and competitive serum protein adsorption. This mechano-guided delivery strategy achieves synergistic “peripheral-central” intervention via a single administration, establishing a paradigm for precision nanomedicine, with broad potential in treating multi-compartment pathologies.