What’s Next after Lipid Nanoparticles? A Perspective on Enablers of Nucleic Acid Therapeutics

Abstract

Recent success of mRNA-based COVID-19 vaccines have bolstered the strength of nucleic acids as a therapeutic platform. The number of new clinical trial candidates is skyrocketing with the potential to address many unmet clinical needs. Despite advancements in other aspects, the systemic delivery of nucleic acids to target sites remains a major challenge. Thus, nucleic acid based therapy has yet to reach its full potential. In this review, we shed light on a select few prospective technologies that exhibit substantial potential over traditional nanocarrier designs for nucleic acid delivery. We critically analyze these systems with specific attention to the possibilities for clinical translation.

Lipid nanoparticle-based formulations for high-performance dentistry applications

“…305,306 Investigated nanolipids are perfect candidates for making them programmable to achieve desired performance, which can be tuned to develop next-generation personalized dentistry treatments. 307,308 However, the possibility and acceptability of this innovative approach to manage dentistry need a special focus supported by public-private collaboration to perform systematic research with the aim to get FDA approval to execute programmable nanolipid for clinical applications.…”

“…To overcome this challenge, polymer-lipid complexes are being designed to provide high encapsulation efficiency along with the narrow size distribution of the hybrid nanostructure system. 307 The bicomponent system consists of a lipid/hydrophobic polymer core where the cargo is loaded with an outer lipid layer for improved biocompatibility. This system has been developed for delivering hydrophobic drugs 313 but structural optimization is required for delivering hydrophilic or charged payload.…”

Nanomaterials for mRNA‐based therapeutics: Challenges and opportunities

“…Unfortunately, toxicity and immunogenicity may be the main obstacles to its clinical application 147 . The cationic lipids, combined with other components forming nanoparticles, are named LNPs 148 . LNPs are the most extensively investigated and clinically advanced delivery system for mRNA‐based therapy 13,149 .…”

Targeted Drug Delivery Using a Plug-to-Direct Antibody–Nanogel Conjugate

“…Targeted drug delivery using antibody–drug conjugates (ADCs) offers the means to specifically kill cancer cells, where the damage to other tissues is greatly reduced compared to traditional chemotherapy. − The ADC approach couples the specificity of monoclonal antibodies with the cytotoxicity of chemotherapeutic drugs, which is leading the new era of targeted cancer therapy with fourteen approved ADCs and more than 100 ADC candidates under clinical evaluation to date. − For example, trastuzumab (Herceptin) antibody has been exploited for its specificity to bind to human epidermal growth factor receptor 2 (HER2) to generate the ADC, Kadcyla (trastuzumab-SMCC-DM1), by conjugating it with the drug emtansine (DM1). This ADC formulation has significantly improved the invasive disease-free survival of HER2-positive breast cancer patients by 50%, compared to trastuzumab alone. , While Kadcyla has been only used for HER2+ breast cancer, , recent approval of sacituzumab govitecan, based on an anti-trophoblast cell-surface antigen 2 (Trop-2) ADC, has broadened the scope of ADCs for pretreated metastatic triple-negative breast cancer (TNBC) patients. , Despite these successes, the clinical potential of ADCs has not been fully realized because of the following: (i) the low drug-to-antibody ratio (DAR) in the current ADC format requires the use of highly toxic drugs, making off-target toxicity a significant limitation and (ii) the antibody–drug linker stability and degradability requirements make their design laborious and limit the drugs that are amenable to be an ADC component. ,, Efforts to overcome such drawbacks include utilizing peptides, aptamers, or folate receptors as the targeting moieties .…”