Despite lipid nanoparticles' (LNPs) success in the effective and safe delivery of mRNA vaccines, an inhalationbased mRNA therapy for lung diseases remains challenging. LNPs tend to disintegrate due to shear stress during aerosolization, leading to ineffective delivery. Therefore, LNPs need to remain stable through the process of nebulization and mucus penetration, yet labile enough for endosomal escape. To meet these opposing needs, we utilized PEG lipid to enhance the surficial stability of LNPs with the inclusion of a cholesterol analog, β-sitosterol, to improve endosomal escape. Increased PEG concentrations in LNPs enhanced the shear resistance and mucus penetration, while β-sitosterol provided LNPs with a polyhedral shape, facilitating endosomal escape. The optimized LNPs exhibited a uniform particle distribution, a polyhedral morphology, and a rapid mucosal diffusion with enhanced gene transfection. Inhaled LNPs led to localized protein production in the mouse lung without pulmonary or systemic toxicity. Repeated administration of these LNPs led to sustained protein production in the lungs. Lastly, mRNA encoding the cystic fibrosis transmembrane conductance regulator (CFTR) was delivered after nebulization to a CFTR-deficient animal model, resulting in the pulmonary expression of this therapeutic protein. This study demonstrated the rational design approach for clinical translation of inhalable LNP-based mRNA therapies.

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An efficient I2-catalyzed cascade coupling protocol was developed for the synthesis of pyrrolo[1,2-a]quinoxaline and imidazo[1,5-a]quinoxaline derivativesviasp3and sp2C–H cross-dehydrogenative coupling.

Nanoparticles (NPs) adsorb proteins when exposed to biological fluids, forming a dynamic protein corona that affects their fate in biological environments. A comprehensive understanding of the protein corona is lacking due to the inability of current techniques to precisely measure the full corona in situ at the single‐particle level. Herein, we introduce a 3D real‐time single‐particle tracking spectroscopy to “lock‐on” to single freely diffusing polystyrene NPs and probe their individual protein coronas, primarily using bovine serum albumin (BSA) as a model system. The fluorescence signals and diffusive motions of the tracked NPs enable quantification of the “hard corona” using mean‐squared displacement analysis. Critically, this method's particle‐by‐particle nature enabled a lock‐in‐type frequency filtering approach to extract the full protein corona, despite the typically confounding effect of high background signal from unbound proteins. From these results, the dynamic in situ full protein corona is observed to contain twice the number of proteins compared to the ex situ‐measured “hard” protein corona.

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A series of 1,4-thiazepin-5(4H)-one derivatives were synthesized via a transition metal-free one-pot Smiles rearrangement process at room temperature. Regioselective seven-membered heterocycles were constructed in good to excellent yields. To gain an in-depth understanding of the S-N type Smiles rearrangement mechanism, a theoretical study was also performed by quantum chemistry calculations.

Nanoparticles (NPs) adsorb proteins when exposed to biological fluids, forming a dynamic protein corona that affects their fate in biological environments. A comprehensive understanding of the protein corona is lacking due to the inability of current techniques to precisely measure the full corona in situ at the single‐particle level. Herein, we introduce a 3D real‐time single‐particle tracking spectroscopy to “lock‐on” to single freely diffusing polystyrene NPs and probe their individual protein coronas, primarily using bovine serum albumin (BSA) as a model system. The fluorescence signals and diffusive motions of the tracked NPs enable quantification of the “hard corona” using mean‐squared displacement analysis. Critically, this method's particle‐by‐particle nature enabled a lock‐in‐type frequency filtering approach to extract the full protein corona, despite the typically confounding effect of high background signal from unbound proteins. From these results, the dynamic in situ full protein corona is observed to contain twice the number of proteins compared to the ex situ‐measured “hard” protein corona.

A high‐speed 3D microscope has been developed to quantify the nanoparticle protein corona at the single‐particle level. As presented by Xiaochen Tan and Kevin Welsher in their Research Article on page 22359, the microscope can “lock on” to freely diffusing nanoparticles to quantify the tightly bound “hard” and dynamic “soft” corona layers. This method can analyze single nanoparticles in the presence of significant protein background signals, opening the possibility for quantifying the protein corona in vivo.