Short-chain dense brush PEGylation on rigid nanocarriers overcomes anti-PEG antibody recognition for immune-stealth drug delivery.

The clinical utility of PEGylated nanomedicines is constrained by anti-polyethylene glycol (PEG) immunity, which drives accelerated blood clearance and infusion reactions. We address this by rationally tuning polymer architecture: a short-chain, high-density PEG brush (PEG500) grafted onto rigid mesoporous silica nanoparticles (MSNs). This design limits immune recognition through three synergistic features: (i) shortened PEG chains reduce epitope accessibility, (ii) high grafting density (4.43 chains/nm2) provides a strong steric barrier, and (iii) the rigid silica surface minimizes PEG backfolding/burial. At equivalent PEG concentrations, ELISAs revealed near-background binding of anti-PEG IgG (6.3) and IgM (AGP3) to MSN-PEG500, in sharp contrast to the strong recognition of PEG2000-based Lipodox. Antibody binding scaled with chain length (PEG2000 > PEG1000 > PEG500), consistent with increased epitope exposure on longer chains, while the compact PEG500 brush on MSNs largely abrogated detection. In vivo, radiolabeled MSN-PEG500 showed prolonged circulation and up to 25 %ID/g tumor uptake at 24 h. In robustly anti-PEG-immunized mice, doxorubicin-loaded MSN-PEG500 preserved antitumor efficacy with 100 % survival, whereas Lipodox (PEG2000) induced fatal hypersensitivity. Mechanistic studies implicated complement activation in PEG2000-associated immunotoxicity; C3 blockade with compstatin attenuated hypothermia (median ΔT reduced from ∼10 °C to ∼2 °C) in sensitized hosts. These findings indicate that nanoscale control of PEG conformation governs immune recognition and safety, offering a clinically tractable blueprint for engineering immune-evasive nanotherapeutics.