pH-Responsive Pathway-Controlled Layer-by-Layer Self-Shedding Nanoparticles for Endothelial Barrier Repair and Efficient Tumor-Targeted Therapy

The nanoparticle-induced endothelial leakiness effect can enhance the ability of nanoparticles (NPs) to cross the vascular barrier but also promote pathological processes. The rarity of NPs capable of endothelial penetration without adverse effects underscores a critical challenge. Addressing this, we designed a bivalve pH-responsive pathway that controlled self-shedding NPs. At its core lies a composite structure comprising indocyanine green-doped spiky SiO2 NPs within an inner-shell comprising the cationic polymer polyethylenimine (PEI), tethered to the core via hydrazone linkages, alongside the inclusion of the endothelial recovery factor angiopoietin-1 (Ang1) and an outermost biomimetic cell membrane shell. In drug delivery, our NPs can target and traverse the endothelial barrier. Then, the initiation of the first self-shedding process ensues upon exposure to an acidic milieu, eliciting the proton sponge effect facilitated by PEI, thereby inducing membrane rupture and enabling NP release, while at the same time, Ang1 is released to repair the disrupted endothelial barrier. Furthermore, the hydrazone bonds were broken in the more acidic environment closer to the tumor site to realize the second self-shedding process, which reproduced the spiky morphology for promoted endocytosis. Therefore, the designed self-shedding NPs can realize two steps of self-shedding to inhibit tumor metastasis and improve photothermal therapy.