Summary: To test this hypothesis I synthesized and characterized molecules to increase nanoparticle binding to cells and enhance DNA escape from the endosome. I also characterized CNS barriers to nanoparticle distribution infused by a procedure called convection enhanced delivery (CED). To enhance non-viral gene delivery, low pH sensitive PEG lipids that stabilize fusogenic liposomes were characterized. The kinetics of pH-triggered collapse of PODS2000 (PEG = 2000Da) and PODS750 (PEG = 750Da) phosphatidylethanolamine liposomes conform to a "minimum surface shielding" model, whereby a critical PEG surface coverage stabilizes the bilayer. Below about 2.5% POD, the exposure of a PE surface induces particle collapse and promotes transfection. To increase cell internalization, a peptide (TATp) was attached to liposomes, either at the phospholipid-aqueous interface or separated by a PEG linker. Both TATp lipids promote cell surface binding and internalization. When infused by CED, liposome distribution depends upon diameter and surface charge. Neutral liposomes accumulate in perivascular cells within the brain. These cells eliminate neutral liposomes from the interstitial fluid with a 9.9 +/- 2.0 hr half-life as determined by elimination of a degradable radiolabeled lipid and by analysis of the time dependent distribution of fluorescence. A non-biodegradable lipid remains within these cells for at least two days. Positive surface charge (10% by mole lipid) dramatically reduces nanoparticle distribution from the infusion site. Incorporation of TATp-PEG-lipid into nanolipoparticles containing DNA, increased binding to and transfection of tumor cells following CED to an intracranial tumor. These results support my hypothesis that better designed non-viral gene vectors will overcome limitations to distribution and transfection within the CNS and suggest that optimization of CED using nanoparticulates will require a strategy to control particle binding and clearance by cells within the CNS.