NanoRNP Overcomes Tumor Heterogeneity in Cancer Treatment

Abstract

Tumor heterogeneity has been one of the most important factors leading to the failure of conventional cancer therapies due to the accumulation of genetically distinct tumor-cell subpopulations during the tumor development process. Due to the diversity of genetic mutations during tumor growth, combining the use of multiple drugs has only achieved limited success in combating heterogeneous tumors. Herein, we report a novel antitumor strategy that effectively addresses tumor heterogeneity by using a CRISPR/Cas9-based nanoRNP carrying a combination of sgRNAs. Such nanoRNP is synthesized from Cas9 ribonucleoprotein, any combinations of required sgRNAs, and a rationally designed responsive polymer that endows nanoRNP with high circulating stability, enhanced tumor accumulation, and the efficient gene editing in targeted tumor cells eventually. By carrying a combination of sgRNAs that targets STAT3 and RUNX1, the nanoRNP exhibited efficient gene expression disruptions on a heterogeneous tumor model with two subsets of cells whose proliferations were sensitive to the reduced expression of STAT3 and RUNX1, respectively, leading to the effective growth inhibition of the heterogeneous tumor. Considering the close relationship between tumor heterogeneity and cancer progression, resistance to therapy, and recurrences, nanoRNP provides a feasible strategy to overcome tumor heterogeneity in the development of more advanced cancer therapy against malignant tumors.

Visualization nanozyme based on tumor microenvironment “unlocking” for intensive combination therapy of breast cancer

“…S10C). The growth status of representative nude mice in each group at the time interval of 0, 3,6,9,12,15,18,21,24,27, and 30 days throughout the treatment period was observed ( Fig. 7C and fig.…”

“…The heterogeneity of breast cancer tissue usually makes it easy to cause multidrug resistance of tumor, tumor recurrence, or metastasis, which leads to the decline of therapeutic effect (2). The principal reason is that there are differences from genotype to phenotype in the same tumor, resulting in different sensitivity, growth speed, in vasion ability, prognosis, and other aspects of tumor cells to drugs (3)(4)(5). A more accurate combination therapy based on tumor heterogeneity could give full play to the maximum effect, produce minimum side effects, and avoid the occurrence of multidrug resist ance (6)(7)(8).…”

Nanovesicle-Mediated Delivery Systems for CRISPR/Cas Genome Editing

“…In another study, a pH-sensitive derivative of polylysine-g-poly(ethylene glycol) was developed for delivery of Cas9/sgRNA ribonucleoprotein targeting STAT3 [129]. Specifically, a 2,5-dihydro-2,5-dioxofuran-3-acetic acid linkage was inserted between poly-L-lysine and PEG to induce breakdown of the grafted polymer, PLys 100 -CAmPEG 77 , at the tumor microenvironment pH.…”

“…(E) pH-responsive polymeric nanoparticle for Cas9/sgRNA RNP delivery. Adapted from[129], ACS, 2019. (F) Physical delivery of Cas9/sgRNA RNP using a microfluidic chip system.…”

Calixarene‐Embedded Nanoparticles for Interference‐Free Gene–Drug Combination Cancer Therapy

“…In physiological environment, CENP has a PEGylated shell and negatively charged to avoid immune clearance and undesired accumulation to normal tissues. [ 12 ] As entering the tumor acidic microenvironment, the decomposition of the CA groups induces rapid separation of the polymer shell and the release of the cationic CEPC, thereby enhancing the tumor accumulation and cellular internalization of CENP. [ 13 ] Furthermore, CAC4A offers a steric barrier to avoid the interference between the molecular drugs and the therapeutic genes loaded in CENP, thus facilitating the combinational therapeutic efficacy and alleviating side effects.…”