Mononuclear phagocyte system blockade for enhanced liposome-assisted metabolic glycan labeling and circulating biomarker detection in mice

Abstract The rapid clearance of nanoparticles by the mononuclear phagocyte system (MPS) severely compromises nanocarrier delivery efficiency and reduces the isolation yield of circulating biomarkers such as nucleosome-bound cell-free DNA (cfDNA) and exosomes. While liposome-based preconditioning is a promising strategy for transient MPS blockade, effective formulations remain scarce. Here, we report a potent MPS-blocking liposome (the Blocker) identified through an integrated screening strategy combining in vitro Kupffer cell uptake assays with in vivo biodistribution profiling. Notably, even upon co-administration, the Blocker effectively extended the circulation half-life of a widely used FDA-approved PEGylated liposomal carrier by 2.1 folds, based on which liposome-assisted metabolic glycan labeling was significantly enhanced in a mouse tumor model. Furthermore, liposomal MPS blockade markedly inhibited the clearance of endogenous circulating cfDNA and exosomes, leading to a 6.8-fold increase in recovered cfDNA yield. This work highlighted liposomal blockade as a versatile platform for improving nanoparticle delivery and liquid biopsy sensitivity.