In this review, we discussed the establishment of a so-called "theranostic" system by instituting the basic principles including the use of: [1] magnetic iron oxide nanoparticles (MION)-based drug carrier; [2] intra-arterial (I.A.) magnetic targeting; [3] macromolecular drugs with unmatched therapeutic potency and a repetitive reaction mechanism; [4] cell-penetrating peptide-mediated cellular drug uptake; and [5] heparin/protamine-regulated prodrug protection and tumor-specific drug re-activation into one single drug delivery system to overcome all possible obstacles, thereby achieving a potentially non-invasive, magnetic resonance imaging-guided, clinically enabled yet minimally toxic brain tumor drug therapy. By applying a topography-optimized I.A. magnetic targeting to dodge rapid organ clearance of the carrier during its first passage into the circulation, tumor capture of MION was enriched by >350 folds over that by conventional passive enhanced permeability and retention targeting. By adopting the prodrug strategy, we observed by far the first experimental success in a rat model of delivering micro-gram quantity of the large β-galactosidase model protein selectively into a brain tumor but not to the ipsi- or contra-lateral normal brain regions. With the therapeutic regimens of most toxin/siRNA drugs to fully (>99.9%) eradicate a tumor being in the nano-molar range, the prospects of reaching this threshold become practically accomplishable.