Chiral Polyproline Enables Functional Stealth for Simultaneous Long Circulation and Endoplasmic Reticulum-Targeted...

Stealth polymer modification is a cornerstone strategy to prolong nanomedicine circulation. However, traditional stealth polymers typically rely on hydration layers or flexible structures to achieve passive antifouling, which is accompanied by intrinsic functional inertness. Here, we report a "functional stealth" strategy using polyproline (PP), a natural amino acid polymer. By leveraging its intrinsic chirality and highly ordered polyproline II (PPII) helical structure, we actively regulate both the in vivo fate and intracellular trafficking of nanoparticles. We engineered gold nanoparticles (AuNPs) modified with l-polyproline (PLP) or d-polyproline (PDP) and demonstrated that L-type AuNPs exhibit superior stealth performance in the blood. Mechanistically, the L-type surface preferentially recruits dysopsonins while inhibiting opsonin adsorption, effectively evading rapid clearance by hepatic and splenic macrophages. Remarkably, the PPII helix of PLP allowed it to selectively "hijack" the endoplasmic reticulum (ER) resident chaperone HSP47, endowing the nanoparticles with intrinsic ER-targeting capability that was absent in conventional inert stealth materials. Leveraging this, we developed chiral nanovaccines by loading tumor antigen peptides onto chiral AuNPs. The L-type surface structure promotes vaccine accumulation within the ER, enhancing antigen entry into the MHC I presentation pathway. This significantly improves antigen presentation efficiency, elicits potent antigen-specific cellular immunity, and suppresses tumor growth. In conclusion, this study elucidates how surface chiral topology can program nanoparticle fate and immune function at the molecular level. PLP represents a paradigm of "functional stealth" polymers, showing that designing surface structures with specific biorecognition properties can simultaneously evade nonspecific clearance and activate targeted intracellular functions.