Multi‐Responsive “Turn‐On” Nanocarriers for Efficient Site‐Specific Gene Delivery In Vitro and In Vivo

Abstract

Systemic gene delivery is a complicated and multistep process that confronts numerous biological barriers. It remains a formidable challenge to exploit a single gene carrier with multiple features to combat all obstacles collectively. Herein, a multi-responsive "turn-on" polyelectrolyte complex (DNA/OEI-SS /HA-SS-COOH, DSS) delivery system is demonstrated with a sequential self-assembly of disulfide-conjugated oligoethylenimine (OEI-SS ) and disulfide bond-modified hyaluronic acid envelope (HA-SS-COOH) that can combat multiple biological barriers collectively when administered intravenously. DSS is designed to effectively accumulate at the tumor tissue and to be internalized into tumor cells by recognizing CD44. The multi-responsive "turn-on" DSS can respond to the alterations of hyaluronidases and glutathione at both the tumor site and at the intracellular milieu. Sequential degradation and detachment of the HA-SS-COOH envelope followed by the dissociation of the OEI-SSx/DNA inner core contributes to the activation of the endosomal escape and gene release functions, thus greatly enhancing nuclear gene delivery. A systematic investigation of DSS has revealed that the tumor accumulation ability, internalization, and endosome escape of the DSS nanocarriers, DNA unpacking and nuclear transportation are all remarkably improved by the multi-responsive "turn-on" design resulting in highly efficient gene transfection in vitro and in vivo.

Synthesis, Radiolabelling and In Vitro Imaging of Multifunctional Nanoceramics

“…While a homogeneous distribution of the particles is seen in the blue and green channels with 405 nm excitation, aggregates of the fluorescent probes are particularly visible in the green and red channels using 488 nm and 561 nm excitation. Such aggregates might be caused by a dynamic interaction between the particles and endosomes/lysosomes, as recently reported by Gu and collaborators …”

“…The major component, τ1, is likely derived mainly from the core of the iron oxide nanocrystals. The difference in lifetimes suggests that the intra‐cellular environment may influence the aggregation of the fluorescent NPs within cellular compartments …”

Construction and application of a liver cancer-targeting drug delivery system based on core–shell gold nanocages

“…The tumors and major organs (livers, hearts, lungs, spleens and kidneys) were collected and immersed into 4% paraformaldehyde for 24 h. Afterward, they were encapsulated in paraffin and sectioned for histologic analysis by hematoxylin and eosin (H&E) staining. 39,40 statistical analysis…”

“…Therefore, AuNCs can be used as photothermal agents. 40,41 To evaluate the potential of the AuNCs-PM-HA for PTT, the AuNCs-PM-HA solution (AuNCs content at 40 μg/mL) was exposed to NIR laser (808 nm, 1.5 W/cm 2 , 10 min). The results show that the temperature of AuNCs-PM-HA solution rose significantly within 5 min and then was maintained stably at 42°C ( Figure 3C).…”

Recent Advances in Stimulus‐Responsive Nanocarriers for Gene Therapy

“…At the same time, intelligent regulation may be carried out during the process of gene delivery to overcome obstacles such as poor gene loading capacity, weak endosome/lysosome escape ability, slow gene release, high vector toxicity, and difficult nuclear transport, with the ultimate goal of improving the efficacy of gene transfection. [ 228 , 232 ] However, the stability of multiple stimuli‐responsive nanocarriers is poor, the preparation process and therapeutic mechanism are complex and the toxicity of the carrier is relatively high. Moreover, deletion of one stimulus may lead to the failure of the entire gene delivery system.…”