Physiological pH Transition‐Driven Protein Corona Dynamics Regulate Cellular Uptake and Inflammatory Responses of Silica Nanoparticles

Physiological pH transitions modulate protein corona dynamics on nanoparticles, altering their cellular uptake and inflammatory responses. Acidic pHs enhance protein adsorption, induce structural changes, and promote cellular uptake. Simultaneously, inflammatory responses are reduced due to altered protein composition, including decreased immunoglobulins and complement proteins and increased regulatory proteins. These findings provide critical insights for understanding the bio‐fate of nanomedicines. Abstract Protein corona alters the biological identities and interactions of nanoparticles with cells, needing to be thoroughly scrutinized before in vivo applications. Importantly, protein corona is evolving as nanoparticles cross different microenvironments, leading to unpredictable biological behaviors. Unveiling how physiological conditions change, especially pH changes associated with tumor‐targeted delivery, affect protein corona composition and subsequent bio‐interactions, is thus essential for understanding the bio‐fate and therapeutic efficacy of nanomedicines. This study investigates how physiological pH transitions influence protein corona dynamics on silica nanoparticles, cellular uptake, and inflammatory responses. Incubating nanoparticle‐protein corona complexes at different pH values reveals that acidic pH increases protein adsorption and induces structural changes of adsorbed proteins, enhancing uptake by macrophages (RAW264.7 and dTHP‐1) and tumor cells (A549) due to reduced electrostatic repulsion and enhanced membrane interactions. Despite increased uptake at acidic pHs, inflammatory responses of dTHP‐1 cells are reduced as indicated by lower levels of reactive oxygen species and pro‐inflammatory cytokines (e.g., IL‐1β, TNF‐α, and IL‐6). This is consistent with altered protein corona composition, featuring decreased levels of complement protein C3 and immunoglobulins, and increased regulatory proteins (e.g., C4BPA). These findings highlight the crucial role of microenvironmental pH in modulating protein corona fingerprints and in vivo behaviors of nanomedicines. Physiological pH transitions modulate protein corona dynamics on nanoparticles, altering their cellular uptake and inflammatory responses. Acidic pHs enhance protein adsorption, induce structural changes, and promote cellular uptake. Simultaneously, inflammatory responses are reduced due to altered protein composition, including decreased immunoglobulins and complement proteins and increased regulatory proteins. These findings provide critical insights for understanding the bio-fate of nanomedicines. Abstract Protein corona alters the biological identities and interactions of nanoparticles with cells, needing to be thoroughly scrutinized before in vivo applications. Importantly, protein corona is evolving as nanoparticles cross different microenvironments, leading to unpredictable biological behaviors. Unveiling how physiological conditions change, especially pH changes associated with tumor-targeted delivery, affect protein corona composition and subsequent bio-interactions, is thus essential for understanding the bio-fate and therapeutic efficacy of nanomedicines. This study investigates how physiological pH transitions influence protein corona dynamics on silica nanoparticles, cellular uptake, and inflammatory responses. Incubating nanoparticle-protein corona complexes at different pH values reveals that acidic pH increases protein adsorption and induces structural changes of adsorbed proteins, enhancing uptake by macrophages (RAW264.7 and dTHP-1) and tumor cells (A549) due to reduced electrostatic repulsion and enhanced membrane interactions. Despite increased uptake at acidic pHs, inflammatory responses of dTHP-1 cells are reduced as indicated by lower levels of reactive oxygen species and pro-inflammatory cytokines (e.g., IL-1 β, TNF- α, and IL-6). This is consistent with altered protein corona composition, featuring decreased levels of complement protein C3 and immunoglobulins, and increased regulatory proteins (e.g., C4BPA). These findings highlight the crucial role of microenvironmental pH in modulating protein corona fingerprints and in vivo behaviors of nanomedicines. Advanced Science, Volume 12, Issue 43, November 20, 2025.