Size- and Surface- Dual Engineered Small Polyplexes for Efficiently Targeting Delivery of siRNA

Abstract

Though siRNA-based therapy has achieved great progress, efficient siRNA delivery remains a challenge. Here, we synthesized a copolymer PAsp(-N=C-PEG)-PCys-PAsp(DETA) consisting of a poly(aspartate) block grafted with comb-like PEG side chains via a pH-sensitive imine bond (PAsp(-N=C-PEG) block), a poly(l-cysteine) block with a thiol group (PCys block), and a cationic poly(aspartate) block grafted with diethylenetriamine (PAsp(DETA) block). The cationic polymers efficiently complexed siRNA into polyplexes, showing a sandwich-like structure with a PAsp(-N=C-PEG) out-layer, a crosslinked PCys interlayer, and a complexing core of siRNA and PAsp(DETA). Low pH-triggered breakage of pH-sensitive imine bonds caused PEG shedding. The disulfide bond-crosslinking and pH-triggered PEG shedding synergistically decreased the polyplexes’ size from 75 nm to 26 nm. To neutralize excessive positive charges and introduce the targeting ligand, the polyplexes without a PEG layer were coated with an anionic copolymer modified with the targeting ligand lauric acid. The resulting polyplexes exhibited high transfection efficiency and lysosomal escape capacity. This study provides a promising strategy to engineer the size and surface of polyplexes, allowing long blood circulation and targeted delivery of siRNA.

Unprotonatable and ROS‐Sensitive Nanocarrier for NIR Spatially Activated siRNA Therapy with Synergistic Drug Effect

“…several strategies including targeting ligand modification, [5][6][7][8] size engineering, [9,10] tunable surface charge, [11][12][13] and sheddable polyethylene glycol (PEG) strategies, [14][15][16] which substantially enhance siRNA therapy effect. However, non-specific gene inhibition in normal tissues remains a limitation for siRNA therapy, which is due to the uncontrolled distribution of siRNA in vivo.…”

“…Small interfering RNA (siRNA) molecules have been extensively explored to treat many diseases including cancer and liver diseases due to their highly efficient target gene silencing. [ 1–4 ] siRNA delivery efficiency has been greatly improved through several strategies including targeting ligand modification, [ 5–8 ] size engineering, [ 9,10 ] tunable surface charge, [ 11–13 ] and sheddable polyethylene glycol (PEG) strategies, [ 14–16 ] which substantially enhance siRNA therapy effect. However, non‐specific gene inhibition in normal tissues remains a limitation for siRNA therapy, which is due to the uncontrolled distribution of siRNA in vivo.…”

A Glutathione‐Responsive Luminescence Sensor Based on Dual‐Emissive Persistent Luminescent Nanoparticles for Ratiometric Tumor Imaging

“…Although ultra-small PLNP, which are less than 10 nm in size, have fast metabolism and short circulating halflife, they have a short retention time at lesion sites, which is not conducive to bioimaging. [12] Therefore, it is urgent to develop a microenvironment responsive PLNP-based intelligent ratiometric sensor with simple preparation, specific ratio signal and controllable size for precise tumor diagnosis.…”

“…In addition, the dual‐emissive PLNP‐based imaging system presents a constant luminescence ratio at the lesion site and normal tissue, resulting in the unavoidable interference of positive signal. Although ultra‐small PLNP, which are less than 10 nm in size, have fast metabolism and short circulating half‐life, they have a short retention time at lesion sites, which is not conducive to bioimaging [12] . Therefore, it is urgent to develop a microenvironment responsive PLNP‐based intelligent ratiometric sensor with simple preparation, specific ratio signal and controllable size for precise tumor diagnosis.…”