Red blood cell-conjugated biomimetic nanomedicine for enhanced therapy of non-small cell lung cancer

<b>Rationale:</b> Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are a standard therapy for non-small cell lung cancer (NSCLC). Despite their clinical efficacy, dose-limiting systemic toxicity and the eventual development of acquired resistance limit their long-term benefit. Therefore, innovative drug delivery strategies are highly demanded to optimize the therapeutic window, minimizing toxicity of EGFR-TKIs at lower doses without compromising their efficacy. <b>Methods:</b> We developed a red blood cell (RBC)-based biomimetic platform for the systemic delivery of EGFR-TKIs. Osimertinib-loaded poly(lactic-co-glycolic acid) nanoparticles were camouflaged with a biotinylated RBC membrane (Osi-RNPs). They were then conjugated to the surface of RBCs <i>via</i> high-affinity biotin-streptavidin interactions to form a stable construct (Osi-RNP-SA-RBC). The physicochemical characteristics, cellular uptake, and <i>in vitro</i> antitumor activity of Osi-RNPs were characterized. We further assessed the pharmacokinetics, biodistribution, therapeutic efficacy, and safety profile of Osi-RNP-SA-RBC in subcutaneous and orthotopic NSCLC mouse models. <b>Results:</b> The Osi-RNP-SA-RBC platform demonstrated stable attachment, favorable hematocompatibility and excellent biosafety. Compared to the Osi-RNP-RBC (nonspecific adsorption), Osi-RNP-SA-RBC presented prolonged blood circulation (1.6-fold) and enhanced tumor accumulation (2.2-fold). Upon intravenous injection of Osi-RNP-SA-RBC at a reduced dose and frequency, superior tumor suppression was observed in both subcutaneous (16.8-fold increase) and orthotopic (4.2-fold increase) NSCLC mouse models compared to the free osimertinib at same administration dosage. <b>Conclusion:</b> This study demonstrates the potential of RBC-conjugated biomimetic nanomedicine as a promising strategy for enhancing the treatment efficiency of EGFR-TKI against NSCLC <i>in vivo</i>.