Core-shell mesoporous silica nanoparticles for gene delivery: Desing principles and strategies to overcome biological barriers

Abstract

ABSTRACT Non-viral nanocarriers are increasingly adopted as safer alternatives to viral vectors for gene delivery, enabling scalability and improved manufacturability. Among them, mesoporous silica nanoparticles (MSiNPs) offer a promising platform due to their structural properties and versatility. This work extracts critical trends of recent literature to seek standardized design rules for MSiNPs-based systems, focusing on the optimisation of the proposed core-shell model architecture. The analysis examines the silica-based matrix core, which determines the morphology and nano-pore structure, and the engineered shell, which modulates the bio-interface through charge inversion, stimulus-responsive release mechanisms, protein corona regulation and active targeting. A formalized “golden-trio” concept is proposed highlighting the interdependence among the physico-chemical properties of MSiNPs, cellular uptake, and intracellular trafficking—key determinants of transfection efficiency. The study evaluates the adaptability of MSiNPs enabling stabilization and vectorization of diverse payloads, including small interfering RNAs and microRNAs for gene silencing, plasmid DNA for expression, and CRISPR/Cas9 systems for genome editing. Strategies for targeting specific cell types by matching surface functionalisation to the genetic payload are discussed, along with the potential for co-administration and theranostic applications to achieve synergistic results. This review concludes that designing the physico-chemical properties of MSiNPs through an integrated approach—combining the core matrix with the precise modulation of the shell surface chemistry to overcome biological barriers and guarantee reproducibility and patient safety—is essential for unlocking their clinical potential in gene therapy.