STAT3 is persistently activated in many types of tumors. It plays a crucial role in tumor growth while turning off the body’s anti-tumor immune response. Silencing STAT3 could therefore have significant implications for improved cancer therapy.  However, as a transcription factor lacking its own enzymatic activity, STAT3 is a challenging target for conventional small molecule drugs.  We developed two siRNA-based targeted delivery platforms.  One is by covalently linking siRNA to the CpG moiety to deliver siRNA to those cells expressing the endosomal Toll-like receptor 9 (TLR9), which recognizes CpG, TLR9’s ligand. The targeted cells are immune cells and a variety of tumor cells.  In addition to serving as a delivery vehicle for the siRNA, CpG’s binding and activation of the TLR9 receptor has its own anti-tumor immunostimulatory effects. CpG-STAT3siRNA is scheduled for phase I trials in B cell lymphoma and glioblastoma.  More recently, we have also generated another siRNA targeted in vivo delivery approach: linking siRNA to CTLA4-aptamer.  We show that CTLA4aptamer-STAT3siRNA is able to silence STAT3 in both tumor-associated T cells and lymphoma tumor cells, inducing potent immune responses as well as direct T cell lymphoma apoptosis.  We are currently exploring the opportunities to use this technology in combination with T cell therapy for lymphomas.  We recently also developed a platform for efficient penetration of antibodies/proteins into cells and nuclei.  Our extensive preliminary studies demonstrated several key therapeutically-relevant features of this new technology: 1) intracellular retention of the antibodies is target dependent and prolonged; 2) both local and systemic administration of the cell-penetrating antibodies at relatively low dosages effectively inhibit intended targets and expression of downstream genes in tumors, resulting in cellular apoptosis and tumor regression in multiple tumor models.  We hope to make numerous critical yet challenging targets amenable through intracellular delivery of antibodies.