Long-term, in vivo therapeutic effects of a single dose of miR-145 micelles for atherosclerosis

Atherosclerosis is a chronic inflammatory disease that is characterized by the build-up of lipid-rich plaques in the arterial walls. The standard treatment for patients with atherosclerosis is statin therapy aimed to lower serum lipid levels. Despite its widespread use, many patients taking statins continue to experience acute events. Thus, to develop improved and alternative therapies, we previously reported on microRNA-145 (miR-145 micelles) and its ability to inhibit atherosclerosis by targeting vascular smooth muscle cells (VSMCs). Importantly, one dose of miR-145 micelles significantly abrogated disease progression when evaluated two weeks post-administration. Thus, in this study, to evaluate how long the sustained effects of miR-145 micelles can be maintained and towards identifying a dosing regimen that is practical for patients with chronic disease, the therapeutic effects of a single dose of miR-145 micelles were evaluated for up to two months in vivo. After one and two months post-treatment, miR-145 micelles were found to reduce plaque size and overall lesion area compared to all other controls including statins without causing adverse effects. Furthermore, a single dose of miR-145 micelle treatment inhibited VSMC transdifferentiation into pathogenic macrophage-like and osteogenic cells in plaques. Together, our data shows the long-term efficacy and sustained effects of miR-145 micelles that is amenable using a dosing frequency relevant to chronic disease patients.

Peptide-based targeting of immunosuppressive cells in cancer

Cancer progression is marked by the infiltration of immunosuppressive cells,such as tumor-associated macrophages(TAMs),regulatory T lymphocytes(Tregs),and myeloid-derived suppressor cells(MDSCs).These cells play a key role in abrogating the cytotoxic T lymphocyte-mediated(CTL)immune response,allowing tumor growth to proceed unabated.Furthermore,targeting these immunosuppressive cells through the use of peptides and peptide-based nanomedicine has shown promising results.Here we review the origins and functions of immunosuppressive cells in cancer progression,peptide-based systems used in their targeting,and explore future avenues of research regarding cancer immunotherapy.The success of these studies demonstrates the importance of the tumor immune microenvironment in the propagation of cancer and the potential of peptide-based nanomaterials as immunomodulatory agents.

Design and in vivo characterization of kidney-targeting multimodal micelles for renal drug delivery

One in three Americans is at risk for developing chronic kidney disease （CKD） and end-stage renal disease （ESRD）, leading to the need for dialysis or a kidney transplant. Small-molecule drugs have been proposed as therapies to manage kidney diseases, but high dosages are often required to achieve therapeutic efficacy, generating off-target side effects, some of which are lethal. To address these limitations, we developed a novel kidney-targeting multimodal micelle （KM） system for drug delivery applications. SpecificaU~ we incorporated the kidney-targeting peptide （Lysine-Lysine-Glutamic acid-Glutamic acid-Glutamic acid）3-Lysine） （（KKEEE）3K） into micelles. This peptide binds to megalin, a multi-ligand cell surface receptor present on renal tubule cells. When incubated with human kidney proximal tubule cells, KMs were found to be biocompatible in vitro. In vivo, KMs showed higher accumulation in the kidneys as compared to a non-targeted （NT） control upon intravenous injection in wild-type C57BL/6J mice. Histological evaluation showed no signs of tissue damage, while blood urea nitrogen （BUN） and creatinine levels were within normal ranges, validating the preservation of kidney health upon micelle administration. To our knowledge, this is the first utilization of （KKEEE）BK in a nanoparticle formulation, and our study offers strong evidence that this novel nanoparticle platform can be used as a candidate drug delivery carrier to direct therapeutics to diseased tissue in CKD.

Clinical progress of nanomedicine-based RNA therapies

The clinical application of nanoparticles(NPs)to deliver RNA for therapy has progressed rapidly since the FDA approval of Onpattro®in 2018 for the treatment of polyneuropathy associated with hereditary transthyretin amyloidosis.The emergency use authorization or approval and widespread global use of two mRNA-NP based vaccines developed by Moderna Therapeutics Inc.and Pfizer-BioNTech in 2021 has highlighted the translatability of NP technology for RNA delivery.Furthermore,in clinical trials,a wide variety of NP formulations have been found to extend the half-life of RNA molecules such as microRNA,small interfering RNA,and messenger RNA,with limited safety issues.In this review,we discuss the NP formulations that are already used in the clinic to deliver therapeutic RNA and highlight examples of RNA-NPs which are currently under evaluation for human use.We also detail NP formulations that failed to progress through clinical trials,in hopes of guiding future successful translation of nanomedicine-based RNA therapeutics into the clinic.