nosa  bacterial pulmonary cystic fibrosis infections, adhere to  pulmonary mucus and do not effectively reach sites of  infections after drug administration. Previously, for nano› particle formulations, the ability to encapsulate soluble APis  and control release had been limited to liposomal formula› tions; and while some liposomes can be loaded by a mecha› nism of transfer across the liposome bilayer and precipita› tion inside the liposome, this technique is not available for  highly ionic API’s such as the antibiotics considered herein.  Therefore, the ion pairing approach presented herein pro› vides a powerful new tool for encapsulation of API’s that  was not previously available.  [0051]  Pharmaceutical companies can apply the disclosed  technology to enhance drug-based therapies that are already  in the market. Pharmaceutical companies can also apply this  technology to enable drug therapies to satisfy clinical trial  objectives that would be otherwise not met.  [0052]  The controlled delivery of active therapeutic ingre› dients from nanocarriers can result in improved bioavail› ability, reduced toxicity, sustained activity, simplified dosing  regimens, improved patient adherence, and enhanced overall  efficacy [Solaro, R., F. Chiellini, and A. Battisti, Targeted  Delivery of Protein Drugs by Nanocarriers.  Materials,  2010.  3(3): p. 1928-1980.]. NC formulations (e.g., nanoparticles)  can be used to target delivery, and then to release cargo at the  desired site. NC formation through direct precipitation  methods is attractive because these methods form NCs, e.g.,  rapidly form active pharmaceutical ingredient (API) nano› particles, with high mass loadings in a scalable and con› tinuous fashion, as in the case of Flash NanoPrecipitation  (FNP) [Immordino, M.  L., F. Dosio, and L. Cattel, Stealth  liposomes: review of the basic science, rationale, and clini› cal applications, existing and potential.  International Jour› nal of Nanomedicine,  2006. 1(3): p. 297-315; Steichen, S.  D., M. Caldarera-Moore, and N. A. Peppas, A review of  current nanoparticle and targeting moieties for the delivery  of cancer therapeutics.  European Journal of  Pharmaceutical  Sciences,  2013. 48(3): p. 416-427.; Galindo-Rodriguez, S.  A., et al.,  Polymeric nanoparticles for oral delivery of drugs  and vaccines: a critical evaluation of in vivo studies. Criti› cal Reviews in Therapeutic Drug Carrier Systems,  2005.  22(5): p. 419-464.]. In nanoprecipitation processes, APis,  e.g., hydrophobic APis, may be dissolved in organic sol› vents and mixed with water as an antisolvent to induce  precipitation and NC self-assembly. However, such direct  precipitation methods are only feasible for water insoluble  compounds (Log P>4), and cannot be used to encapsulate  hydrophilic peptides and biologics into NC form. Water  soluble biologics may be encapsulated through water-in-oil› in-water emulsion (W/O/W) or liposomal processes that  require multiple steps, suffer from poor encapsulation effi› ciencies, or exhibit low drug mass loadings [Li, S.-D. and  L.  Huang, Pharmacokinetics and Biodistribution of Nanopar› ticles.  Molecular Pharmaceutics,  2008. 5(4): p. 496-504;  Owens Iii, D. E. and N. A. Peppas, Opsonization, biodistri› bution, and pharmacokinetics of polymeric nanoparticles.  International Journal of Pharmaceutics,  2006. 307(1): p.  93-102; Pattni, B. S.,  V. V. Chupin, and V. P. Torchilin, New  Developments in Liposomal Drug Delivery.  Chemical  Reviews,  2015. 115(19): p. 10938-10966.]. The new meth› ods set forth herein, which efficiently encapsulate hydro› philic APis into nanocarriers using direct water precipitation  methods, can expand the nanocarrier API pharmacokinetic  (PK) and/or pharmacodynamics (PD) properties that can be  achieved.  [0053]  Engineering of API water solubilities can enable  new processing methods for nanocarrier encapsulation. This  can be performed by reversible covalent conjugation of APis  with hydrophobic molecules, which results in the production  of a hydrophobic prodrug. After encapsulation and delivery,  covalent linkages are cleaved, thereby producing the origi› nal API for therapeutic activity. However, covalent modifi› cation of APis results in the creation of a new molecular  entity, which requires additional comprehensive, costly, and  time-consuming testing for Food & Drug Administration  (FDA) approval. API salt form engineering is an alternative  route to tune API water solubility. In this process, charged  functional groups on the API are ion-paired with a counter  ion to produce a API with transiently altered solubilities. An  advantage of salt form engineering is that resultant products  are not considered new molecular entities, and do not require  full FDA reapproval. However, in most instances, API salt  forms are screened and engineered for enhanced water  solubility. The alternative use of hydrophobic ion-pairs to  create hydrophobic salt forms is a non-conventional method  to increase API hydrophobicity. This technique has been  used for the precipitation of weakly hydrophobic small  molecules (c Log P=2-5) into nanocarriers, but not for  highly water soluble (c Log P>0) and positively charged  biologics. In this text, hydrophobic ion pairing is demon› strated to encapsulate highly soluble, positively charged  antibiotic biologics, such as gentamycin (c Log P=-4.21)  and polymyxin B (c Log P=-5.6). The ion pairs (IPs) are  processed into stable nanocarriers through Flash NanoPre› cipitation, a continuous and scalable water precipitation  process. A priori, it might have been expected that such  biologics could not be precipitated in water with hydropho› bic ion-pairs, because of their high API water solubilities.  The chemical identities of ion pairs, rules governing pre› cipitation, and processing methods that can give rise to API  salts with the desired solubilities for encapsulation were  previously unknown.  [0054]  Previously, ion pairing has been used to formulate  nanoparticles from hydrophobic compounds. These are  defined by having log P values greater than 1, 2, 3, 4, or 5  at neutral pH [Pinkerton, N. M., et al., Formation of stable  nanocarriers by in situ ion pairing during block-copolymer  directed rapid precipitation. Molecular pharmaceutics, 2013.  10(1): p. 319-328]. For example, Song et. al [Song,  Y.  H., et  al., A novel in situ hydrophobic ion pairing (HIP) formula› tion strategy for clinical product selection of a nanoparticle  drug delivery system. Journal of Controlled Release, 2016.  229: p. 106-119.] used ion pairing for AZD281, which had  a log P of2 at a neutral pH of7.Another group ofresearchers  has complexed proteins and polymeric charged species with  oppositely charged polymeric compounds with high solu› bility. High solubility could mean log P values less than -2  and/or solubilities in aqueous media of over 10 mg/ml at  pH=7. Patel and Guadana [Gaudana, R., et al., Design and  evaluation of a novel nanoparticulate-based formulation  encapsulating a HIP complex of lysozyme. Pharmaceutical  development and technology, 2013. 18(3): p. 752-759; Patel,  A., R. Gaudana, and A. K. Mitra, A novel approach for  antibody Nanocarriers development through hydrophobic  ion-pairing complexation. Journal of Microencapsulation,  2014. 31(6): p. 542-550] showed that soluble antibody or  US 2020/0268679 Al  5  Aug. 27, 2020 