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The setback in the practical clinical use of RNA interference (RNAi)-based cancer treatment stems from the lack of targeted small interfering RNA (siRNA) delivery. Here, we show that luteinizing hormone-releasing hormone (LHRH) analog-tethered multi-layered polyamidoamine (PAMAM) nanoconstructs silence the anti-apoptotic MCL-1 gene in LHRH receptor overexpressing human breast (MCF-7) and prostate cancer (LNCaP) cells with 70.91 % and 74.10 % efficiency, respectively. These results were confirmed by RT-PCR. The Acridine orange/Ethidium bromide (AO/EB) dual staining revealed that the silencing of MCL-1 induced apoptosis in both the cell lines. In vivo tumor regression studies performed using MCF-7 and LNCaP xenografted severe combined immunodeficiency (SCID) mice demonstrated highly improved tumor regression in groups treated with targeted nanoconstructs complexed with MCL-1 …