LAUSR

The safe administration of thrombolytic agents is a challenge for the treatment of acute thrombosis. Lipid‐based nanoparticle drug delivery technologies present opportunities to overcome the existing clinical limitations and deliver thrombolytic therapy with enhanced therapeutic outcomes and safety. Herein, lipid cubosomes are examined as nanocarriers for the encapsulation of thrombolytic drugs. The lipid cubosomes are loaded with the thrombolytic drug urokinase‐type plasminogen activator (uPA) and coated with a low‐fouling peptide that is incorporated within a metal–phenolic network (MPN). The peptide‐containing MPN (pep‐MPN) coating inhibits the direct contact of uPA with the surrounding environment, as assessed by an in vitro plasminogen activation assay and an ex vivo whole blood clot degradation assay. The pep‐MPN‐coated cubosomes prepared with 22 wt% peptide demonstrate a cell membrane‐dependent thrombolytic activity, which is attributed to their fusogenic lipid behavior. Moreover, compared with the uncoated lipid cubosomes, the uPA‐loaded pep‐MPN‐coated cubosomes demonstrate significantly reduced nonspecific cell association (<10% of the uncoated cubosomes) in the whole blood assay, a prolonged circulating half‐life, and reduced splenic uPA accumulation in mice. These studies confirm the preserved bioactivity and cell membrane‐dependent release of uPA within pep‐MPN‐coated lipid cubosomes, highlighting their potential as a delivery vehicle for thrombolytic drugs.