Cocktail Strategy Based on NK Cell-Derived Exosomes and Their Biomimetic Nanoparticles for Dual Tumor Therapy

Abstract

Successful cancer therapy requires drugs being precisely delivered to tumors. Nanosized drugs have attracted considerable recent attention, but their toxicity and high immunogenicity are important obstacles hampering their clinical translation. Here we report a novel “cocktail therapy” strategy based on excess natural killer cell-derived exosomes (NKEXOs) in combination with their biomimetic core–shell nanoparticles (NNs) for tumor-targeted therapy. The NNs were self- assembled with a dendrimer core loading therapeutic miRNA and a hydrophilic NKEXOs shell. Their successful fabrication was confirmed by transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). The resulting NN/NKEXO cocktail showed highly efficient targeting and therapeutic miRNA delivery to neuroblastoma cells in vivo, as demonstrated by two-photon excited scanning fluorescence imaging (TPEFI) and with an IVIS Spectrum in vivo imaging system (IVIS), leading to dual inhibition of tumor growth. With unique biocompatibility, we propose this NN/NKEXO cocktail as a new avenue for tumor therapy, with potential prospects for clinical applications.

Nanoparticle-Based Delivery of Tumor Suppressor microRNA for Cancer Therapy

“…MiRNAs are naturally encapsulated and transported by EVs; consequently, EVs are an emerging exciting contender for use as delivery vehicles to introduce TS miRNA at the tumor site. In this review, EVs from a variety of cell sources are discussed, including mesenchymal stem cells (MSCs), natural-killer (NK) cells, tumor cells and monocytes [12][13][14][15].…”

“…PAMAM dendrimers have been utilised to encapsulate TS miRNA for delivery to the tumor site. Most inorganic based NPs are modified by conjugation with antibodies [19,20], or encapsulated in natural vesicles [15], to produce NPs with clinically relevant properties, including tumor-targeting ability. This review focuses on a variety of both natural and synthetic nanoparticle (NP) delivery vehicles that have been employed for tumor-targeted delivery of TS miRNA in vivo.…”

“…This study did not investigate the therapeutic efficacy of miR-133b delivery but showed the feasibility of TS miRNA encapsulation in a lipid formulation and its accumulation in the lungs in vivo. Neuroblastoma miR-34a Silica nanoparticles IV Significant reduction in tumor growth [19] let-7a NN/NK-EV cocktail IV Significantly lower tumor bioluminescence signal [15] Melanoma lung metastases miR-34a and siRNAs LPH nanoparticles with ScFv IV Co-delivery of miRNA and siRNA additively suppressed tumor growth [20] Colorectal liver metastases miR-655-3p and OXL NCPs IP Suppression of liver tumor development [32] Colorectal cancer miR-204-5p and OXL Silica nanoparticles IV Therapeutic agents combined had best therapeutic efficacy [33] Liver cancer miR-122 BOMB nanoparticles IV Lower tumor volumes in treatment group [34] miR-34a Liposomal formulation IV Tumor growth inhibited [35] OPMD miR-185 MSC-EVs Topical Reduced the incidence of transformation to OSCC [36] Pancreatic cancer miR-634 LNPs IV Significant reduction in tumor growth [37] Subsequently, the same group employed cationic lipoplexes to deliver miR-29b into the lung tumor environment in a mouse model of the disease [27]. MiR-29b has been shown to be downregulated in many cancers, including lung cancer, with its molecular targets including DNA methyltransferases (DNMT) [38].…”

“…Polyamidoamine (PAMAM) dendrimers of repetitively branched amide and amine units show great versatility as the building blocks of miRNA delivery vehicles. PAMAM dendrimer-based nanoparticles were used to deliver let-7a to neuroblastoma tumors in a NOD/SCID murine model [15]. The NP formulation consisted of PAMAM dendrimer (NN) linked to let-7a and labelled with Cy-5 to allow fluorescent imaging.…”

“…The rationale of using NK-EVs was that they could provide more targeted delivery efficiency due to the presence of the CXCR4 receptor on NK-EV, which encourages migration to target cells, including those in the brain. Bioluminescent imaging showed that mice treated with the NP cocktail had suppression of tumor growth [15].…”