The rapid development of CRISPR/Cas9
systems has opened up tantalizing prospects to sensitize cancers to
chemotherapy using efficient targeted genome editing, but safety concerns
and possible off-target effects of viral vectors remain a major obstacle
for clinical application. Thus, the construction of novel nonviral
tumor-targeting nanodelivery systems has great potential for the safe
application of CRISPR/Cas9 systems for gene–chemo-combination
therapy. Here, we report a polyamidoamine-aptamer-coated hollow mesoporous
silica nanoparticle for the co-delivery of sorafenib and CRISPR/Cas9.
The core–shell nanoparticles had good stability, enabled ultrahigh
drug loading, targeted delivery, and controlled-release of the gene–drug
combination. The nanocomplex showed >60% EGFR-editing efficiency
without off-target effects in all nine similar sites, regulating the
EGFR-PI3K-Akt pathway to inhibit angiogenesis, and exhibited a synergistic
effect on cell proliferation. Importantly, the co-delivery nanosystem
achieved efficient EGFR gene therapy and caused 85% tumor inhibition
in a mouse model. Furthermore, the nanocomplex showed high accumulation
at the tumor site in vivo and exhibited good safety
with no damage to major organs. Due to these properties, the nanocomplex
provides a versatile delivery approach for efficient co-loading of
gene–drug combinations, allowing for precise gene editing and
synergistic inhibition of tumor growth without apparent side effects
on normal tissues.
Nanotechnology has emerged as an ideal approach for achieving the efficient chemo agent delivery. However, the potential toxicity and unclear internal metabolism of most nano-carriers was still a major obstacle for the clinical application. Herein, a novel “core‒shell” co-assembly carrier-free nanosystem was constructed based on natural sources of ursolic acid (UA) and polyphenol (EGCG) with the EpCAM-aptamer modification for hepatocellular carcinoma (HCC) synergistic treatment. As the nature products derived from food-plant, UA and EGCG had good anticancer activities and low toxicity. With the simple and “green” method, the nanodrugs had the advantages of good stability, pH-responsive and strong penetration of tumor tissues, which was expected to increase tumor cellular uptake, long circulation and effectively avoid the potential defects of traditional carriers. The nanocomplex exhibited the low cytotoxicity in the normal cells
in vitro,
good biosafety of organic tissues and efficient tumor accumulation
in vivo
. Importantly, UA combined with EGCG showed the immunotherapy by activating the innate immunity and acquired immunity resulting in significant synergistic therapeutic effect. The research could provide new ideas for the research and development of self-assembly delivery system in the future, and offer effective intervention strategies for clinical HCC treatment.
The combination of chemotherapy and photothermal therapy displays improved anti-cancer effects and lower systematic toxicity of a free drug compared with monotherapy.
The nanocarrier-based delivery system has emerged as a promising candidate for cancer therapy; nevertheless, their quality problems, variation between batches, and carrier-related toxicity issues have restricted their clinical utilization. Compared with traditional carrier-based nanoparticles, carrier-free nanodrug delivery systems preferred to overcome all these drawbacks and will have a wide range of applications in biomedicine and nanotechnology. Herein, we developed a novel carrier-free nanodrug Asp-UA consisted of the classical drug aspirin and the natural plant drug UA via a green and simple approach. The Asp-UA NPs were investigated for shape, particle size, zeta potential, stability, and UV−vis spectroscopy absorption. Cellular uptake study showed that Asp-UA NPs could be easily internalized by HepG2 cells; cellular study demonstrated that Asp-UA NPs held better inhibitory efficiency on tumor metastasis with low toxicity in vitro and in vivo. Moreover, Asp-UA NPs could obviously suppress the progress of cancer metastasis by H22 cells in vivo. Overall, Asp-UA NPs possess a variety of advantages and hold promise to become an alternative to the treatment of cancer metastasis.
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