nanoporous silica particles were synthesized and characterized as described previously and as detailed in supplementary figure 1 and the supplementary methods section .
particles larger than 150-nm in diameter were removed via differential centrifugation or size - exclusion chromatography ( see supplementary figs . 1a and 1d ) .
protocells were formed by fusing 120-nm liposomes to the nanoporous core as reported previously , and the composition of the slb was optimized to reduce non - specific binding associated with cationic and , to a lesser extent , anionic lipids ( see supplementary fig . 5 ) .
zwitterionic lipids ( dopc or dppc ) with 5 wt% phosphatidylethanolamine ( dope or dppe , respectively ) , 5 wt% peg-2000 pe ( 18:0 or 16:0 , respectively ) , and 30 wt% cholesterol were used in all further studies ; pegylated lipids were incorporated into the liposomes used for fusion and are , therefore , expected to be present on both the inner and outer leaflets of the slb .
the size of the nanoporous core was also optimized to attain a balance between achievable cargo capacity and the rate of protocell internalization ( see supplementary fig .
9 ) ; nanoparticles 100- to 150-nm in diameter were employed in the delivery of drugs , drug cocktails , sirna cocktails , and protein toxins .
the nanoporous cores were soaked in a 10 mm solution of cargo(s ) for 1 - 12 hours prior to liposome fusion ; individual components of the surrogate cargo mixture ( fig .
the rates of cargo release were optimized by incorporating various percentages of aeptms , an amine - containing silane , into the sol used to form nanoporous cores ( see supplementary fig .
particles containing 15 wt% aeptms were used to deliver drugs and drug cocktails ( fig .
6 ) , while particles containing 20 wt% aeptms were used to deliver the multicomponent mixture ( fig .
5 ) , the sirna cocktail ( supplementary figs . 13 and 14 ) , and diphtheria toxin a - chain ( supplementary figs . 15 and 16 ) .
 encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine . to realize this potential , however 
 , targeted nanocarriers must simultaneously overcome multiple challenges , including specificity , stability , and a high capacity for disparate cargos . 
 here we report porous nanoparticle - supported lipid bilayers ( protocells ) that synergistically combine properties of liposomes and nanoporous particles . 
 protocells modified with a targeting peptide that binds to human hepatocellular carcinoma ( hcc ) exhibit a 10,000-fold greater affinity for hcc than for hepatocytes , endothelial cells , and immune cells . 
 furthermore , protocells can be loaded with combinations of therapeutic ( drugs , sirna , and toxins ) and diagnostic ( quantum dots ) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos . 
 the enormous capacity of the high - surface - area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer allow a single protocell loaded with a drug cocktail to kill a drug - resistant hcc cell , representing a 106-fold improvement over comparable liposomes . 
Methods Summary
Supplementary Material