Sequence-regulated, lung-targeting heteropolypeptide nanoparticles via in situ erythrocyte hitchhiking

Targeted lung delivery of therapeutics is critical for various respiratory diseases. However, the rational design of lung-targeting nanocarriers through fine-tuning of polymeric structures remains challenging. Herein, we reported the development of lung-targeting, heteropolypeptide-grafted nanoparticles (NPs), whose targeting ability was dependent on the copolymer sequence that mediated in situ erythrocyte hitchhiking. Specifically, the incorporation of β-branched amino acid residues in poly(_L-glutamic acid)s, like valine and isoleucine, resulted in gradient copolymer sequence with terminal hydrophobic segments. The corresponding heteropolypeptide-decorated NPs with hydrophobic coronas thus showed high affinity to red blood cell membranes, leading to accumulation in lung tissues at up to 37% of the injected dose through erythrocyte hitchhiking. This strategy mediated effective lung-targeting of CeO₂, showing anti-oxidant effect that alleviated pulmonary inflammation to treat acute lung injury. This work highlights the importance of copolymer sequence in tuning the biodistribution of polymer-decorated NPs, shedding light on the design of nanocarriers for pulmonary delivery.