Strategies for Nanomaterials to Circumvent the Mononuclear Phagocyte System

Nanomaterials (NMs) have emerged as promising tools for tumor-targeted therapy and gene editing. However, their delivery efficiency is severely limited by the mononuclear phagocyte system (MPS), which rapidly clears them from circulation primarily in the liver and spleen. This remains a major bottleneck for the clinical translation of nanomedicine. In order to break through this challenge, this review systematically summarizes main categories of strategies designed to circumvent MPS clearance. First, we discuss the strategies of engineering NMs to evade MPS recognition, including modulation of physicochemical property control, surface engineering strategy, and cell-based delivery systems. Second, we analyze the strategies that transiently modulate the MPS function itself, including macrophage blockade, phagocytosis inhibition, and macrophage depletion. These approaches collectively aim to reduce nonspecific clearance, thereby enhancing the accumulation of NMs at the target site. Finally, we further discuss the opportunities and remaining challenges in this field. This review is expected to provide a valuable reference for advancing the biomedical application of nanomaterials.