Xinxin Yan

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.

Living drug delivery system has been proposed as new concept materials because it is able to communicate with biological system, sense subtle changes in body microenvironment caused by disease, and then make rapid response to cure in the early stage of disease. Herein, taking full advantage of the tumor hypoxia physiology and successive effects of photodynamic therapy (PDT), we designed a new living delivery system via combining the PDT and hypoxia-responsive chemotherapy, abbreviated as Ce6-PEG-Azo-PCL. Then, according to the fact that oxygen can be converted into reactive oxygen species during irradiation of the photosensitizer, tumor cells could be killed after the poly(ethylene glycol) (PEG) conjugated photosensitizer chlorine e6 was irradiated at the tumor site. What is more, the continuous consumption of oxygen could further amplify the hypoxia condition of tumor and trigger the disassembly of hypoxia-responsive azobenzene bridges at the tumor site to release loaded chemotherapeutics drugs doxorubicin. The ongoing collaboration with PDT and hypoxia-responsive chemotherapy provided an integrated therapeutic effect in vitro and in vivo to suppress tumor growth.

Limited cellular uptake and inefficient intracellular drug release severely hamper the landscape of polymer drug nanocarriers in cancer chemotherapy. Herein, to address these urgent challenges in tumor treatment simultaneously, we integrated the multivalent choline phosphate (CP) and bioreducible linker into a single polymer chain, designed and synthesized a neoteric bioreducible polymer nanocarrier. The excellent hydrophility of these zwitterionic CP groups endowed high drug loading content and drug loading efficiency of doxorubicin to this drug delivery system (∼22.1 wt %, ∼95.9%). Meanwhile, we found that the multivalent choline phosphate can effectively enhance the internalization efficiency of this drug-loaded nanocarrier over few seconds, and the degree of improvement depended on the CP density in a single polymer chain. In addition, after these nanocarriers entered into the tumor cells, the accelerated cleavage of bioreducible linker made it possible for more cargo escape from the delivery system to cytoplasm to exert their cytostatic effects more efficiently. The enhanced therapeutic efficacy in various cell lines indicated the great potential of this system in anticancer drug delivery applications.

Unlocking the full potential of mRNA immunotherapy necessitates targeted delivery to specific cell subsets in the spleen. Four-component lipid nanoparticles (LNPs) utilized in numerous clinical trials are primarily limited in hepatocyte and muscular targeting, highlighting the imperative demand for targeted and simplified non-liver mRNA delivery systems. Herein, we report the rational design of one-component ionizable cationic lipids to selectively deliver mRNA to the spleen and T cells with high efficacy. Unlike the tertiary amine-based ionizable lipids involved in LNPs, the proposed cationic lipids rich in secondary amines can efficiently deliver mRNA both in vitro and in vivo as the standalone carriers. Furthermore, these vectors facilitate efficacious mRNA delivery to the T cell subsets following intravenous administration, demonstrating substantial potential for advancing immunotherapy applications. This straightforward strategy extends the utility of lipid family for extrahepatic mRNA delivery, offering new insights into vector development beyond LNPs to further the field of precise mRNA therapy.