Abstract
<jats:p>Poly(ethylene glycol) (PEG) is the standard stealth polymer to functionalize lipid nanoparticle (LNP) surfaces, requiring conjugation to a lipid tail for anchoring in the LNP’s shell. We eliminate the need for lipid conjugates by introducing a new polymer-only design principle using function-encoded statistical polymers. For that, we synthesized statistical amphiphilic copolymers in which hydrophobic units are followed by hydrophilic units, with the intention that the hydrophobic units of the polymer anchor to the LNP surface, and its hydrophilic parts stealth the particle surface. We screened the formulation space using a 42-member poly(2-oxazoline) library, yielding design rules for successful LNP formulations. Cryogenic transmission electron microscopy confirmed the intact LNP structure, and biological activity was assessed in multiple human cell types differentiated from inducible pluripotent stem cells. Intravenously administered barcoded LNPs formulated with function-encoded statistical polymers compared to the equivalent PEG-lipid LNPs showed 2.5- and 5-fold higher amounts in mice and lower bloodstream levels, leading to significantly higher accumulation in the spleen and liver. Rather than assembling LNP interfaces from multiple molecular components, this work establishes that orthogonal interfacial functions can be encoded directly into the architecture of a single statistical polymer, providing a general molecular design principle for programmable nanomedicine interfaces.</jats:p>