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Hydrophobic drugs in organic solvent are mixed with an aqueous suspension of amph-NPs and dialyzed to remove the organic solvent leading to partitioning of the drug into the hydrophobic pockets of the amph-NP ligand shell. This approach allows loading of a wide variety of drugs nearly insoluble in aqueous solutions - a highly desirable feature as many molecules currently being investigated as new pharmaceuticals, though potent, well-defined, and cost effective, are hydrophobic, and, therefore, rapidly cleared in vivo, thus requiring high and often toxic doses to achieve a desired effect. This technology dramatically reduces off-target delivery and toxicity and allows cargo to be utilized more effectively and at a lower dose, thereby potentially increasing the maximum allowable clinical dose for improved therapeutic efficiency. Furthermore, these NPs are less than 5nm, which allows for efficient clearance renally preventing long-term tissue accumulation. The Inventors performed a single subcutaneous injection near the base of the tail in mice and found 10% of the total injection dose in the draining lymph node - a 12-fold increase in NP lymph node accumulation compared to control PEG-NPs.