Surface chemistry governs sex-dependent responses to PEG and zwitterionic NPs

Zwitterionic polymers are emerging as promising PEG alternatives, but their performance is rarely evaluated in primary immune cells or across biological sexes. Here, we synthesized pH-responsive PEG- and zwitterion-grafted cationic nanoparticles, including PEG methyl ether methacrylate (PEGMMA), carboxybetaine methacrylate (CBMA), sulfobetaine DMAPS, and polymeric PDMAPS, and assessed their cytotoxicity and siRNA delivery in primary male and female murine macrophages.

All formulations enabled intracellular siRNA uptake and suppressed tumor necrosis factor–α (TNF-α) expression. However, sex-dependent effects varied by surface chemistry and biological endpoint: zwitterionic nanoparticles exhibited sex-specific effects in cytotoxicity and gene silencing despite similar uptake, whereas PEGMMA showed higher uptake in females but comparable knockdown across sexes. These findings demonstrate that uptake alone does not predict functional efficacy and highlight the importance of sex-informed evaluation when developing nanomedicines.