RESUMO
Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy. The first monoclonal antibody authorized for treating human epidermal growth receptor 2 (HER2)-positive breast cancer is trastuzumab. However, resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes. To address this issue, tumor microenvironment (TME) pH-responsive nanoparticles (NPs) were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer (BCa). This nanoplatform is comprised of a methoxyl-poly (ethylene glycol)-b-poly (lactic-co-glycolic acid) copolymer with a TME pH-liable linker (Meo-PEG-Dlink m -PLGA) and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction. When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously, they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface. With the intracellular mRNA release to up-regulate PTEN expression, the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells, thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.
RESUMO
The in vitro transcribed (IVT) mRNA technology has progressed rapidly and the application of mRNA vaccines in the COVID-19 pandemic made it become the most talked-about topic. Compared with protein drugs, IVT mRNA has a lower cost; it can be modular produced and its sequence can be modified easily, so it has a broad application prospect. However, due to its short history, mRNA drugs face the problem of lacking sufficient clinical data, and there is no quality control standard for mRNA drugs except mRNA vaccines. We overview the sequence design, delivery vectors, administration, application prospect and safety considerations of mRNA drugs. We also discussed the quality control of mRNA drugs briefly.
RESUMO
Messenger RNA (mRNA) has drawn much attention in the medical field. Through various treatment approaches including protein replacement therapies, gene editing, and cell engineering, mRNA is becoming a potential therapeutic strategy for cancers. However, delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake. Therefore, in addition to mRNA modification, efforts have been devoted to developing nanoparticles for mRNA delivery. In this review, we introduce four categories of nanoparticle platform systems: lipid, polymer, lipid-polymer hybrid, and protein/peptide-mediated nanoparticles, together with their roles in facilitating mRNA-based cancer immunotherapies. We also highlight promising treatment regimens and their clinical translation.
RESUMO
Patients exhibit good tolerance to messenger ribonucleic acid (mRNA) vaccines, and the choice of encoded molecules is flexible and diverse. These vaccines can be engineered to express full-length antigens containing multiple epitopes without major histocompatibility complex (MHC) restriction, are relatively easy to control and can be rapidly mass produced. In 2021, the U.S. Food and Drug Administration (FDA) approved the first mRNA-based coronavirus disease 2019 (COVID-19) vaccine produced by Pfizer and BioNTech, which has generated enthusiasm for mRNA vaccine research and development. Based on the above characteristics and the development of mRNA vaccines, mRNA cancer vaccines have become a research hotspot and have undergone rapid development, especially in the last five years. This review analyzes the advances in mRNA cancer vaccines from various perspectives, including the selection and expression of antigens/targets, the application of vectors and adjuvants, different administration routes, and preclinical evaluation, to reflect the trends and challenges associated with these vaccines.