Combinatory modulation of the physical and biochemical characteristics of nanocarrier delivery systems is an emergent topic in the field of nanomedicine. Here, we studied the combined effects of incorporation of active targeting moieties into nanocarriers and their morphology affecting the enhanced permeation and retention effect for nanomedicine cancer therapy. Self-assembled lipid discoidal and vesicular nanoparticles with low-polydispersity sub-50 nm size range and identical chemical compositions were synthesized, characterized, and correlated with in vitro cancer cellular internalization, in vivo tumor accumulation and cancer treatments. The fact that folate-associated bicelle yields the best outcome is indicative of the preference for discoidal carriers over spherical carriers and the improved targeting efficacy due to the targeting ligand/receptor binding. The approach is successfully adopted to design the nanocarriers for photodynamic therapy, which yields a consistent trend in in vitro and in vivo efficacy: folate nanodiscs > folate vesicles > nonfolate nanodiscs > nonfolate vesicles. Folate discs not only have shown a higher tumor uptake and photothermal therapeutic efficiency, but also minimize skin photosensitivity side effects. The advantages of nanodiscoidal bicelles as nanocarriers, including well-defined size, robust formation, easy encapsulation of hydrophobic molecules (therapeutics and/or diagnostics), easy incorporation of targeting molecules, and low toxicity, enable the scalable manufacturing of a generalized in vivo multimodal delivery platform.