3 research outputs found
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Surface De-PEGylation Controls Nanoparticle-Mediated siRNA Delivery In Vitro and In Vivo
The present work proposes a unique de-PEGylation strategy for controllable delivery of small interfering RNA (siRNA) using a robust lipid-polymer hybrid nanoparticle (NP) platform. The self-assembled hybrid NPs are composed of a lipid-poly(ethylene glycol) (lipid-PEG) shell and a polymer/cationic lipid solid core, wherein the lipid-PEG molecules can gradually dissociate from NP surface in the presence of serum albumin. The de-PEGylation kinetics of a series of different lipid-PEGs is measured with their respective NPs, and the NP performance is comprehensively investigated in vitro and in vivo. This systematic study reveals that the lipophilic tails of lipid-PEG dictate its dissociation rate from NP surface, determining the uptake by tumor cells and macrophages, pharmacokinetics, biodistribution, and gene silencing efficacy of these hybrid siRNA NPs. Based on our observations, we here propose that lipid-PEGs with long and saturated lipophilic tails might be required for effective siRNA delivery to tumor cells and gene silencing of the lipid-polymer hybrid NPs after systemic administration
Intracellular Mechanistic Understanding of 2D MoS<sub>2</sub> Nanosheets for Anti-Exocytosis-Enhanced Synergistic Cancer Therapy
Emerging two-dimensional (2D) nanomaterials,
such as transition-metal
dichalcogenide (TMD) nanosheets (NSs), have shown tremendous potential
for use in a wide variety of fields including cancer nanomedicine.
The interaction of nanomaterials with biosystems is of critical importance
for their safe and efficient application. However, a cellular-level
understanding of the nano-bio interactions of these emerging 2D nanomaterials
(<i>i</i>.<i>e</i>., intracellular mechanisms)
remains elusive. Here we chose molybdenum disulfide (MoS<sub>2</sub>) NSs as representative 2D nanomaterials to gain a better understanding
of their intracellular mechanisms of action in cancer cells, which
play a significant role in both their fate and efficacy. MoS<sub>2</sub> NSs were found to be internalized through three pathways: clathrin
→ early endosomes → lysosomes, caveolae → early
endosomes → lysosomes, and macropinocytosis → late endosomes
→ lysosomes. We also observed autophagy-mediated accumulation
in the lysosomes and exocytosis-induced efflux of MoS<sub>2</sub> NSs.
Based on these findings, we developed a strategy to achieve effective
and synergistic <i>in vivo</i> cancer therapy with MoS<sub>2</sub> NSs loaded with low doses of drug through inhibiting exocytosis
pathway-induced loss. To the best of our knowledge, this is the first
systematic experimental report on the nano-bio interaction of 2D nanomaterials
in cells and their application for anti-exocytosis-enhanced synergistic
cancer therapy