Messenger RNA (mRNA) has emerged as a transformative technology for combating viral pandemics and malignancies, with lipid nanoparticle (LNP)-based mRNA vaccines playing a pivotal role in the COVID-19 pandemic. However, current LNP face challenges such as low endosomal escape efficiency (<5%), leading to cargo waste and increased costs. To address this, pHLIP-incorporated LNP (mRNA@LNP-pHLIP), leveraging the pH-dependent membrane-insertion properties of pHLIP is developed to enhance endosomal escape. pHLIP undergoes a conformational change in acidic environments, enabling it to insert into endosomal membranes and promote the release of mRNA into the cytosol. In vitro studies demonstrate a three to fivefold increase in mRNA expression across multiple cell lines, while in vivo experiments show sustained and higher protein expression in mice. Applied to a monkeypox vaccine encoding A35R and M1R antigens, mRNA@LNP-pHLIP elicited stronger immune responses, highlighting its potential for next-generation mRNA therapeutics and vaccines.

Caixia Liu et al. Adv Healthc Mater. 2025.

Rebalance of coagulation and anticoagulation to achieve a hemostatic effect has recently gained attention as an alternative therapeutic strategy for hemophilia. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.

Miao Jiang, Fubo Yang, Yajuan Jiang, Lihua Cheng, Jing Han, Jing Yi, Guangwei Zhang, Zhihua Ma, Liying Cao, Bin Zuo, Lixiang Zhou, Lihui Huang, Shuhua Niu, Zhiyong Xia, Xiaoping Zhou, Xiaohui Bai, Nancy L Esmon, Cangping Xia, Lihong Han, Cheng H Esmon, Dawei Wu, Jianxin Xu. Blood. 2023 Sep 21;142(12):1071-1081. doi: 10.1182/blood.2023020005.

Purpose: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. Experimental design: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. Results: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. Conclusions: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Pilié PG, Hung Le et al. Clin Cancer Res. 2024 May 15;30(10):2121-2139. doi: 10.1158/1078-0432.CCR-23-1763.