Nanotoxicity: A Key Obstacle to Clinical Translation of siRNA-Based Nanomedicine

Abstract

siRNAs have immense therapeutic potential for the treatment of various gene-related diseases ranging from cancer, viral infections and neuropathy to autoimmune diseases. However, their bench-to-bedside translation in recent years has faced several challenges, with inefficient siRNA delivery being one of the most frequently encountered issues. In order to improve the siRNA delivery especially for systemic treatment, nanocarriers made of polymers, lipids or inorganic materials have become almost essential. The ‘negative’ aspects of these carriers such as their nanotoxicity and immunogenicity thus can no longer be overlooked. In this article, we will extensively review the nanotoxicity of siRNA carriers. The strategies for mitigating the risks of nanotoxicity and the methodology for evaluating these strategies will also be discussed. By addressing this often overlooked but important issue, it will help clear the way for siRNAs to fulfill their promise as a versatile class of therapeutic agents.

Influence of cationic lipid concentration on properties of lipid–polymer hybrid nanospheres for gene delivery

“…28 High cellular uptake of LPHNSs is an essential qualification for gene transfection. 43 The fluorescently labeled Rho LPHNSs taken up by HeLa cells were quantified as a function of incubation time. The cellular uptake of LPHNSs in all tested groups (A, B, C, and D) was higher than PEI-modified PLGA NSs for the same incubation time.…”

Combined silencing expression of MGMT with EGFR or galectin-1 enhances the sensitivity of glioblastoma to temozolomide

“…Conventional systems such as PEI or lipofectamine ® are widely used in vitro. However, their clinically use is not suitable despite their high efficiency of transfection of siRNA due to their toxicity profiles (34,35).…”

<div>Lipid nanoparticles for targeted siRNA delivery &ndash; going from bench to bedside</div>

“…This recent study is particularly encouraging, as it demonstrates that selection of proper lipid components can overcome earlier reported toxicity, immunogenicity such as the release of tumor necrosis factor-α, interferon-γ, interleukin-6, interleukin-12, and damage to the liver tissue resulting in elevated levels of transaminases (alanine transaminase, aspartate transaminase), leukopenia, and thrombocytopenia. [47][48][49] We want to emphasize that application of siRNA/LNP in clinical studies should be based on predictive animal models and understanding the physiology. Also, sharing data is a key point for successful translation of LNP from a bench scale into clinical studies.…”