Pre-intervention with intravenous immunoglobulin reverses the immunogenic clearance of PEGylated nanomedicines.

Nanomedicines are susceptible to immunogenic clearance before reaching their disease targets, thereby limiting their pharmacodynamic efficacy. To overcome this challenge, PEGylation has been developed and widely used. However, in therapies that necessitate multiple repeated administrations, the immunogenicity of PEGylated nanoparticles often becomes non-negligible, resulting in an accelerated blood clearance (ABC) effect and declining therapeutic efficacy. Here we propose a simple and clinically applicable strategy of pre-intervention with FDA-approved intravenous immunoglobulin (IVIG) before injection of nanoparticles. Pretreatment with IVIG was found to regulate the organism's immunologic macroenvironment and transiently block the mononuclear phagocyte system, thereby circumventing the anti-PEG antibody-mediated clearance of nanomedicines. The universal applicability of the IVIG pretreatment strategy is demonstrated by its consistent reversal of the ABC effect across five structurally diverse nanomaterials, with sizes of 10-120 nm. IVIG significantly enhances therapeutic efficiency in breast tumours, particularly in large tumours (~350 mm3), with up to a 3.9-fold improvement. Overall, pre-intervention with IVIG opens a new paradigm for addressing the immunogenic clearance issue and enhancing the performance of nanomedicines.