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As one of the most frequent complications of critical illness, acute lung injury (ALI) carries a high risk of clinical morbidity and mortality. Cepharanthine (CPA) has significant anti-inflammatory activity, however, due to poor water solubility, low bioavailability, and short half-life, it fails to provide effective clinical management measures. Here, we explored the flexibility of an erythrocyte-anchoring strategy using CPA-encapsulated chitosan-coating nanoparticles (CPA-CNPs) anchored onto circulating erythrocytes for the treatment of ALI. CPA-CNPs adhered to erythrocytes successfully (E-CPA-CNPs) and exhibited high erythrocyte adhesion efficiency (>80%). Limited toxicity and favorable biocompatibility enabled further application of E-CPA-CNPs. Next, the reticuloendothelial system evasion features were analyzed in RAW264.7 macrophages and Sprague-Dawley rats. Compared with bare CPA-CNPs, erythrocyte-anchored CNPs significantly decreased cellular uptake in immune cells and prolonged circulation time in vivo. Notably, the erythrocyte-anchoring strategy enabled CNPs to be delivered and accumulated in the lungs (up to 6-fold). In the ALI mouse model, E-CPA-CNPs attenuated the progression of ALI by inhibiting inflammatory responses. Overall, our results demonstrate the outstanding advantages of erythrocyte-anchored CPA-CNPs in improving the pharmacokinetics and bioavailability of CPA, which offers great promise for a lung-targeted drug delivery system for the effective treatment of ALI. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ivermectin-loaded nanoparticles were delivered to lungs through adsorption on RBCs. • RBC-hitchhiking strategy improved ivermectin pharmacokinetics and bioavailability. • Nanoparticle properties affected the characteristics of RBC-nanoparticles in vivo. Recent studies have demonstrated that ivermectin (IVM) exhibits antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of coronavirus disease 2019 (COVID-19). However, the repurposing of IVM for the treatment of COVID-19 has presented challenges primarily due to the low IVM plasma concentration after oral administration, which was well below IC 50. Here, a red blood cell (RBC)-hitchhiking strategy was used for the targeted delivery of IVM-loaded nanoparticles (NPs) to the lung. IVM-loaded poly (lactic-co-glycolic acid) (PLGA) NPs (IVM-PNPs) and chitosan-coating IVM-PNPs (IVM-CSPNPs) were prepared and adsorbed onto RBCs. Both RBC-hitchhiked IVM-PNPs and IVM-CSPNPs could significantly enhance IVM delivery to lungs, improve IVM accumulation in lung tissue, inhibit the inflammatory responses and finally significantly alleviate the progression of acute lung injury. Specifically, the redistribution and circulation effects were related to the properties of NPs. RBC-hitchhiked cationic IVM-CSPNPs showed a longer circulation time, slower accumulation and elimination rates, and higher anti-inflammatory activities than RBC-hitchhiked anionic IVM-PNPs. Therefore, RBC-hitchhiking provides an alternative strategy to improve IVM pharmacokinetics and bioavailability for repurposing of IVM to treat COVID-19. Furthermore, according to different redistribution effects of different NPs, RBC-hitchhiked NPs may achieve various accumulation rates and circulation times for different requirements of drug delivery. [ABSTRACT FROM AUTHOR]