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.