We have designed and synthesized a family of linear-dendritic hybrid polymers that self-assemble with DNA to yield stable nanostructures with a series of concentric, functional “shells” that can be independently modified to address each of the barriers to efficient gene delivery in turn. For our initial design, we have chosen a system composed of linear poly (ethylene glycol) (PEG) and dendritic poly (amidoamine) (PAMAM). These linear-dendritic diblock copolymers self-assemble with DNA to yield nanoparticles (150 nm) with a core of primary amines for DNA condensation, an inner shell of secondary and tertiary amines to promote endosomal escape, and an outer shell of PEG. These diblock copolymer systems are functionalized with a small molecule targeting ligand, mannose, which is displayed on the outer surface of the particle and directs receptor-mediated uptake by antigen-presenting cells such as macrophages and dendritic cells. In vitro studies demonstrate selective transfection of cells at levels exceeding that of branched PEI in the absence of serum and better than 4-fold more efficiently than PEI in the presence of serum. Moreover, these systems exhibit no measurable toxicity at concentrations 50-fold higher than those at which PEI is toxic. We will also discuss current in vivo studies aimed at exploring the targeted transfection of APC's with accompanying antigen presentation and T-cell activation.