Organ- and Cell-Selective Delivery of mRNA In Vivo Using Guanidinylated Serinol Charge-Altering Releasable Transporters.

Selective RNA delivery is required for the broad implementation of RNA clinical applications, including prophylactic and therapeutic vaccinations, immunotherapies for cancer, and genome editing. Current polyanion delivery relies heavily on cationic amines, while cationic guanidinium systems have received limited attention due in part to their strong polyanion association, which impedes intracellular polyanion release. Here, we disclose a general solution to this problem in which cationic guanidinium groups are used to form stable RNA complexes upon formulation but at physiological pH undergo a novel charge-neutralization process, resulting in RNA release. This new delivery system consists of guanidinylated serinol moieties incorporated into a charge-altering releasable transporter (GSer-CARTs). Significantly, systematic variations in structure and formulation resulted in GSer-CARTs that exhibit highly selective mRNA delivery to the lung (∼97%) and spleen (∼98%) without targeting ligands. Illustrative of their breadth and translational potential, GSer-CARTs deliver circRNA, providing the basis for a cancer vaccination strategy, which in a murine model resulted in antigen-specific immune responses and effective suppression of established tumors.

Visible-Light-Driven Alkyne Hydro-/Carbocarboxylation Using CO2 via Iridium/Cobalt Dual Catalysis for Divergent Heterocycle Synthesis.

We present herein the first visible-light-driven hydrocarboxylation as well as carbocarboxylation of alkynes using CO2 via an iridium/cobalt dual catalysis. Such transformations provide access to various pharmaceutically important heterocycles in a one-pot procedure from readily available alkynes. Coumarins, 2-quinolones, and 2-benzoxepinones were directly accessed through a one-pot alkyne hydrocarboxylation/alkene isomerization/cyclization sequence in which the Ir photocatalyst serves a dual role to promote single-electron transfer in alkyne hydrocarboxylation and energy transfer in the subsequent alkene isomerization. Moreover, an unprecedented cobalt carboxylation/acyl migration cascade enables alkyne difunctionalization to introduce γ-hydroxybutenolides with high efficiency. We expect that this cascade strategy will inspire new perspectives for alkyne and alkene difunctionalization.

Visible-Light-Mediated Metal-Free Difunctionalization of Alkenes with CO2 and Silanes or C(sp3 )-H Alkanes.

Catalytic alkene difunctionalization via Si-H and C-H activations represents an ideal atom- and step-economic pathway for quick assembly of molecular complexity. We herein developed a visible-light-promoted metal-free difunctionalization of alkenes using abundant CO2 and readily available Si-H and C(sp3 )-H bonds as feedstocks. Through the merger of photoredox and hydrogen-atom-transfer catalysis, a variety of value-added compounds, such as ß-silacarboxylic acids and acids bearing a γ-heteroatom (e.g., N, O, S) could be directly accessed from simple alkenes in a redox-neutral fashion.