Kinetically Programmed Thermoresponsive Polyethylene Glycol Shedding from Lipid Nanoparticles Improves mRNA Delivery

Abstract Polyethylene glycol (PEG) can stabilize nanoparticles and facilitate transport across biological barriers, yet the same PEG layer suppresses cellular uptake─a trade-off known as the PEG dilemma. Current strategies seek to overcome this limitation by enabling PEG shedding in response to pathological biochemical cues, but their dependence on heterogeneous microenvironments limits predictability and cross-route applicability. Here, we report a thermoresponsive PEG shedding strategy based on PEG–lipid conjugates with oxanorbornadiene linkers that cleave at physiological temperature. By varying the linker structure, PEG shedding kinetics can be modulated over pharmacologically relevant time scales, enabling mRNA-lipid nanoparticles to undergo surface transitions from sterically shielded to cell-interactive states. In inhaled delivery, rapid PEG shedding after mucus traversal restored cellular uptake and markedly enhanced pulmonary mRNA expression, resulting in inhibition of pulmonary metastases. In systemic administration, intermediate PEG shedding preserved the circulation benefit of dense PEGylation while enabling subsequent intracellular delivery, leading to improved tumor expression and antitumor efficacy. These results establish kinetic programming of PEG shedding as a design principle for dynamically regulating nanoparticle biointerfaces across distinct delivery routes.