A method of fabricating a therapeutic nanoparticle, comprising: a. preparing an aqueous phase; b. adjusting the pH of the aqueous phase; c. mixing an organic phase containing a nanoparticle comprising an amphiphilic polymer and an organic solvent with the aqueous phase; wherein the organic solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), acetonitrile, dimethylformamide, DCM, ethyl acetate and acetone, and wherein the amphiphilic polymer is selected from the group consisting of: poly(lactic acid)-poly(ethylene glycol) (PLA-PEG), poly(lactic-co-glycolic acid)-poly(ethylene glycol), poly(lactic-co-glycolic acid)-d-α-tocopheryl polyethylene glycol succinate, poly(lactic-co-glycolic acid)-ethylene oxide fumarate, poly(glycolic acid)-poly(ethylene glycol), polycaprolactone-poly(ethylene glycol), and a combination thereof; d. partially removing the organic solvent; e. adding a water-insoluble biologically active ingredient, the active ingredient comprising an ionizable group; and f. removing the organic solvent; wherein the active ingredient has a higher water solubility in the adjusted pH than in neutral pH;and wherein the active ingredient comprises a histone deacetylase inhibitor selected from the group consisting of vorinostat (SAHA), istodax, belinostat, apicidin, SBHA, scriptaid, sodium butyrate, trichostatin A, entinostat, panobinostat, mocetinostat, romidepsin, tubastatin A, givinostat, dacinostat, quisinostat, pracinostat, droxinostat, abexinostat, ricolinostat, tacedinaline, tubacin, resminostat, citarinostat, santacruzamate, nexturastat A, tasquinimod, parthenolide, and any pharmaceutically acceptable salts thereof. a. preparing an aqueous phase; b. adjusting the pH of the aqueous phase; c. mixing an organic phase containing a nanoparticle comprising an amphiphilic polymer and an organic solvent with the aqueous phase; wherein the organic solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), acetonitrile, dimethylformamide, DCM, ethyl acetate and acetone, and wherein the amphiphilic polymer is selected from the group consisting of: poly(lactic acid)-poly(ethylene glycol) (PLA-PEG), poly(lactic-co-glycolic acid)-poly(ethylene glycol), poly(lactic-co-glycolic acid)-d-α-tocopheryl polyethylene glycol succinate, poly(lactic-co-glycolic acid)-ethylene oxide fumarate, poly(glycolic acid)-poly(ethylene glycol), polycaprolactone-poly(ethylene glycol), and a combination thereof; d. partially removing the organic solvent; e. adding a water-insoluble biologically active ingredient, the active ingredient comprising an ionizable group; and f. removing the organic solvent; wherein the active ingredient has a higher water solubility in the adjusted pH than in neutral pH;and wherein the active ingredient comprises a histone deacetylase inhibitor selected from the group consisting of vorinostat (SAHA), istodax, belinostat, apicidin, SBHA, scriptaid, sodium butyrate, trichostatin A, entinostat, panobinostat, mocetinostat, romidepsin, tubastatin A, givinostat, dacinostat, quisinostat, pracinostat, droxinostat, abexinostat, ricolinostat, tacedinaline, tubacin, resminostat, citarinostat, santacruzamate, nexturastat A, tasquinimod, parthenolide, and any pharmaceutically acceptable salts thereof. wherein the active ingredient has a higher water solubility in the adjusted pH than in neutral pH;and wherein the active ingredient comprises a histone deacetylase inhibitor selected from the group consisting of vorinostat (SAHA), istodax, belinostat, apicidin, SBHA, scriptaid, sodium butyrate, trichostatin A, entinostat, panobinostat, mocetinostat, romidepsin, tubastatin A, givinostat, dacinostat, quisinostat, pracinostat, droxinostat, abexinostat, ricolinostat, tacedinaline, tubacin, resminostat, citarinostat, santacruzamate, nexturastat A, tasquinimod, parthenolide, and any pharmaceutically acceptable salts thereof.