Sun Hwa Kim

Acute kidney injury (AKI) is a rapid loss of renal function that has become a global health concern, with incidence rates reaching up to 50% in critically

Rationale: Acute liver failure (ALF) is characterized by rapid hepatic dysfunction, primarily caused by drug-induced hepatotoxicity. Due to the lack of satisfactory treatment options, ALF remains a fatal clinical disease, representing a grand challenge in global health.

Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon, making it an ideal approach for treating patients with inflammatory bowel disease. However, multiple physical barriers impede the delivery of oral RNA drugs through the gastrointestinal tract. Herein, we developed a novel oral siRNA delivery system that protects nucleic acids in extreme environments by employing exosomes derived from milk to encapsulate tumor necrosis factor-alpha (TNF-α) siRNA completely. The remarkable structural stability of milk-derived exosomes (M-Exos), as opposed to those from HEK293T cells, makes them exceptional siRNA carriers. Results demonstrate that milk exosomes loaded with TNF-α siRNA (M-Exo/siR) can effectively inhibit the expression of TNF-α-related inflammatory cytokines. Moreover, given that milk exosomes are composed of unique lipids with high bioavailability, orally administered M-Exo/siR effectively reach colonic tissues, leading to decreased TNF-α expression and successful alleviation of colitis symptoms in a dextran sulfate sodium-induced inflammatory bowel disease murine model. Hence, milk-derived exosomes carrying TNF-α siRNA can be effectively employed to treat inflammatory bowel disease. Indeed, using exosomes naturally derived from milk may shift the current paradigm of oral gene delivery, including siRNA.

Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue‐specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor‐targeting peptides into the LNPs; the programmed death ligand 1 (PD‐L1) binding peptides are conjugated to PEGylated lipids via a copper‐free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD‐L1 proteins, which leads to the uptake of LNPs into PD‐L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN‐deficient triple‐negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy‐mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor‐targeted LNPs for mRNA‐based cancer therapy.

Acquired resistance to chemotherapy is a major challenge in the treatment of triple-negative breast cancer (TNBC). Despite accumulated evidence showing microRNA-21 (miR-21) as a vital regulator of tumor progression, the role of miR-21 in modulating the multidrug resistance of TNBC remains obscure. In this study, we demonstrate that miR-21 affects chemoresistance in 4T1 TNBC cells in response to doxorubicin (DOX) by regulating the P-glycoprotein (P-gp) drug efflux pump. Overexpression of miR-21 in the 4T1 cells markedly reduced their sensitivity to DOX, impeding DOX-promoted cell death. We employed anti-miR-21 oligonucleotide conjugated with a PD-L1-binding peptide (P21) for targeted delivery to 4T1 tumor cells. The selective down-regulation of miR-21 in 4T1 TNBC led to the reversal of P-gp-mediated DOX resistance by up-regulating phosphatase and tensin homolog (PTEN). Our study highlights that miR-21 is a key regulator of drug efflux pumps in TNBC, and targeting miR-21 could enhance DOX sensitivity, offering a potential therapeutic option for patients with DOX-resistant TNBC.

Research on siRNA delivery has seen tremendous growth over the past few decades. As one of the major delivery strategies, siRNA bioconjugates offer the potential to enhance and extend the pharmacological properties of siRNAs while minimizing toxicity. In this paper, we suggest the development of a siRNA conjugate platform with peptides and proteins that are ligands of target receptors for cancer treatment. The siRNA bioconjugates target and block the receptor membrane proteins, enter the cells through receptor-mediated endocytosis, and inhibit the expression of that same target membrane receptor, thereby doubly controlling the function of the membrane proteins. The three kinds of bioconjugates targeting CD47, PD-L1, and EGFR were synthesized via two different copper-free click chemistry reactions. Results showed the cellular uptake of each conjugate, reduction of target gene expression, and efficient functional control of receptor proteins. This platform provides an effective approach for regulating membrane proteins in various diseases beyond cancer.