Acute myeloid leukemia (AML) continues to represent a substantial unmet therapeutic need in clinical practice. In recent years, peptide–drug conjugates and small interfering RNA (siRNA) drugs have gained considerable attention due to their impressive clinical progress in treating various diseases. In this study, we designed a carrier-free “3-in-1” peptide–daunorubicin–siRNA (PDR) nanoassembly, which combines a cell-penetrating and tumor-suppressing peptide, a daunorubicin (DNR) prodrug, and siRNA targeting the LILRB4 gene. After optimizing the molar ratio among peptide, DNR prodrug, and siRNA, we identified the most potent PDR formulation, which exhibited excellent intracellular uptake efficiency, primarily through caveolin-mediated endocytosis, in THP-1 cells. The pH-responsive bond in the DNR prodrug facilitated the endosomal escape of siRNA, leading to significant gene repression of LILRB4. Additionally, the tumor-suppressing peptide p16^MIS effectively inhibited the transition of cells from the S phase to the G2/M phase and induced apoptosis. In a leukemia mouse model, PDR efficiently suppressed leukemia cell invasion, prolonged survival, and reduced leukemia cell infiltration in the bone marrow. Notably, silencing LILRB4 not only promoted T cell maturation in spleen and lymph nodes but also enhanced T cell infiltration in tumor tissues. This study offered a highly promising therapeutic strategy for AML and other diseases.

The novel coronavirus disease 2019 (COVID-19) is still rampant all over the world, causing incalculable losses to the world. Major pharmaceutical organizations around the globe are focusing on vaccine research and drug development to prevent further damage caused by the pandemic. The messenger RNA (mRNA) technology has got ample of attention after the success of the two very effective mRNA vaccines during the recent pandemic of COVID-19. mRNA vaccine has been promoted to the core stage of pharmaceutical industry, and the rapid development of mRNA technology has exceeded expectations. Beyond COVID-19, the mRNA vaccine has been tested for various infectious diseases and undergoing clinical trials. Due to the ability of constant mutation, the viral infections demand abrupt responses and immediate production, and therefore mRNA-based technology offers best answers to sudden outbreaks. The need for mRNA-based vaccine became more obvious due to the recent emergence of new Omicron variant. In this review, we summarized the unique properties of mRNA-based vaccines for infectious diseases, delivery technologies, discussed current challenges, and highlighted the prospects of this promising technology in the future. We also discussed various clinical studies as well preclinical studies conducted on mRNA therapeutics for diverse infectious diseases.

Attaching DNA/RNA to nanomaterials is the basis for nucleic acid-based assembly and drug delivery. Herein, we report that small interfering RNA (siRNA) effectively coordinates with ligand-free lanthanide nanoparticles (NaGdF₄ NPs), and forms siRNA/NaGdF₄ spherical nucleic acids (SNA). The coordination is primarily attributed to the interaction between Gd and phosphate backbone of the siRNA. Surprisingly, an efficient encapsulation and rapid endosomal escape of siRNA from the endosome/lysosome were achieved, due to its flexible ability to bound to phospholipid head of endosomal membrane, thereby disrupting the membrane structure. Resorting to the dual properties of NaGdF₄ NPs, siRNA loading, and endosomal escape, siRNA targeting programmed cell death-ligand 1 (siPD-L1)/NaGdF₄ SNA triggers significant gene silencing in vitro and in vivo, and effectively represses the tumor growth in both CT26 tumor model and 4T1 orthotopic murine model.