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.