Zwitterionic polymers have emerged as promising trans-mucus nanocarriers due to their superior antifouling properties. However, for pH-sensitive zwitterionic polymers, the effect of the pH microenvironment on their trans-mucus fate remains unclear. In this work, we prepared a library of zwitterionic polydopamine-modified silica nanoparticles (SiNPs-PDA) with an isoelectric point of 5.6. Multiple-particle tracking showed that diffusion of SiNPs-PDA in mucus with a pH value of 5.6 was 3 times faster than that in mucus with pH value 3.0 or 7.0. Biophysical analysis found that the trans-mucus behavior of SiNPs-PDA was mediated by hydrophobic and electrostatic interactions and hydrogen bonding between mucin and the particles. Furthermore, the particle distribution in the stomach, intestine, and lung demonstrated the pH-mediated mucus penetration behavior of the SiNPs-PDA. This study reveals the pH-mediated mucus penetration behavior of zwitterionic nanomaterials, which provides rational design strategies for zwitterionic polymers as nanocarriers in various mucus microenvironments.
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