Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation.

Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in lipid material structures and compositions to systematically achieve the pulmonary and hepatic (respectively) targeted mRNA distribution and expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation of LNP compositions. Contrary to current LNP paradigms, our findings demonstrate that cholesterol and phospholipid are dispensable for LNP functionality. Specifically, cholesterol-removal addresses the persistent challenge of preventing nanoparticle accumulation in hepatic tissues. By modulating and simplifying intrinsic LNP components, concurrent mRNA accumulation and translation is achieved in the lung and liver, respectively. This targeting strategy is applicable to existing LNP systems with potential to expand the progress of precise mRNA therapy for diverse diseases.

Substance flow analysis on the leachate DOM molecules along five typical membrane advanced treatment processes.

The processes combining biological treatment with membrane separation technologies have been widely adopted for leachate treatment. However, dissolved organic matter (DOM) of leachate membrane concentrates generated from various membrane separation technologies has not been systematically investigated in field scale. Therefore, substance flow analysis based on DOM molecular information of leachate membrane concentrates from primary membrane systems (i.e. nanofiltration (NF) and reverse osmosis (RO)) and secondary membrane systems (i.e. disk-tube reverse osmosis (DTRO) and humic substance filtration system (HSF)) in five engineering-scale leachate treatment facilities, obtained via ultra-performance liquid chromatography coupled with hybrid quadrupole Orbitrap mass spectrometry, was given and simultaneously compared. In NF concentrates (NFC), 45.1-98.5% of DOM originated from raw leachate (L-DOM) was concentrated, showing poor biodegradability. The L-DOM interception characteristics of NFC-fed HSF were mainly based on volume reduction but concentration effect. L-DOM in RO concentrates (ROC) showed a higher proportion of peak intensity reduced components, accounting for 50.3-96.8%, and organic composition changes were more dependent on water quality characteristics than membrane types. ROC-fed DTRO intercepted 49.3-72.6% of L-DOM, but DTRO may be less effective at intercepting DOM molecules in landfill leachate with higher oxidation levels. Considering risks from feasible treatment technologies, the difficulty for the treatment of leachate membrane concentrates followed the order of DTRO concentrates > ROC > NFC. This study suggests that ROC-fed DTRO need to be controlled to avoid amplifying the treatment difficulty. Besides, treatment technologies for RO and DTRO concentrates with low-concentrated but refractory DOM and high salts should be explored.