Despite the availability of guidelines regarding the materials for nanoparticle formulation, guidelines specifying the grade and quality of the starting materials is still lacking and should be provided by the regulatory bodies [401]. From the manufacturing perspective, development of nanopharmaceuticals often requires sophisticated processes involving size reduction (e.g., high pressure homogenization, high energy milling, sonication, extrusion, etc.), purification (e.g., organic solvent removal, centrifugation, filtration, etc.), stabilization (e.g., lyophilization, spray-drying, etc.), sterilization, and so forth [402]. development of long-acting locally and systemically injectable formulations, tuning the onset of the drugs release through the endowment of sensitivity to numerous internal or external stimuli, as well as adjuvancy and immune activation, which is a desired component for injectable vaccines and immunotherapeutic formulations. The current work seeks to provide a comprehensive review IGF2 of all the abovementioned contributions, along with the most recent improvements made within each domain name. Furthermore, recent developments within the domains of passive and active targeting will be briefly debated. strong class=”kwd-title” Keywords: nanotechnology, injectable parenteral formulations, solubility enhancement, controlled release, targeting, adjuvancy, immune activation 1. Introduction Though the word parenteral terminologically refers to the routes of administration that steer clear of the alimentary canal, parenteral delivery in todays health care system mostly entails the injection of the drug through intradermal, subcutaneous, intramuscular, intravenous and intra-arterial pathways. Adjunct to the injectable formulations, parenteral dosage forms also include biodegradable implants, transdermal patches, and ocular delivery systems [1]. The focus of the current review, however, will be mainly the injectable systems commonly used for drug delivery purposes. Notwithstanding the invasiveness, injection remains an indispensable route of delivery for a wide range of active pharmaceutical ingredients (APIs). In addition to advantages such as the quick onset of action, possibility to administer a mixture cGAMP of APIs, and convenience for hospitalized patients with special conditions (e.g., unconscious or orally restricted patients), parenteral administration is usually associated with a wide range of benefits, such as avoiding the hostile gastrointestinal environment, possibility to deliver macromolecular APIs with low gastrointestinal absorption (e.g., proteins and peptides), circumventing the hepatic first pass metabolism, and potential to achieve an extended duration of the therapeutic effect [2,3]. Conventionally, injectable parenteral dosage forms can be formulated as solutions, suspensions or emulsions. The advent and development of nanotechnology, however, has introduced new opportunities to improve the efficiency and elaborate the potentials of these conventional dosage forms [1]. A variety cGAMP of benefits justify the application of nanoparticulate systems for injection-based parenteral drug delivery. These include enhancing the solubility of poorly water-soluble actives, thus improving their bioavailability, developing prolonged release parenteral depots, facilitating targeted delivery to specific organs, tissues, cells, cGAMP or even organelles, and protecting the incorporated cargo from the harsh extra- and intracorporeal conditions [4,5,6,7]. The present review seeks to elaborate on the application of nanostructures for injection-based parenteral drug delivery and the various platforms created within this context. A list of marketed injectable nanomedicine is tabulated in Table 1, while the injectable nanoparticle-based therapeutic formulations going through various stages of clinical trials are presented in Table 2. A significant number of the nanosystems within each category highlights the rapidly growing role of nanotechnology within the domain of injection-based drug delivery. Table 1 Injectable nanomedicine in the market. Adapted with modification from [8,9,10]. thead th align=”center” valign=”middle” style=”border-top:solid thin;border-bottom:solid thin” rowspan=”1″ colspan=”1″ Product /th th align=”center” valign=”middle” style=”border-top:solid thin;border-bottom:solid thin” rowspan=”1″ colspan=”1″ Nanocarrier /th th align=”center” valign=”middle” style=”border-top:solid thin;border-bottom:solid thin” rowspan=”1″ colspan=”1″ API /th th align=”center” valign=”middle” style=”border-top:solid thin;border-bottom:solid thin” rowspan=”1″ colspan=”1″ Indication /th th align=”center” valign=”middle” style=”border-top:solid thin;border-bottom:solid thin” cGAMP rowspan=”1″ colspan=”1″ Function of the Carrier /th th align=”center” valign=”middle” style=”border-top:solid thin;border-bottom:solid thin” rowspan=”1″ colspan=”1″ Approval /th th align=”center” valign=”middle” style=”border-top:solid thin;border-bottom:solid thin” rowspan=”1″ colspan=”1″ Route of Injection /th /thead Abelcet? Amphocil? (Markted name outside USA)Ribbon-like structures of a bilayered membrane and amphotericin BAmphotericin BSystemic fungal infectionMPS targetingFDA 1995C1996IVAbraxane?Albumin-paclitaxel conjugatesPaclitaxelMetastatic breast cancer, non-small-cell lung cancerPassive tumor targeting FDA 2005IVAdagen?Monomethoxypolyethylene glycol (PEG) covalently attached to the adenosine deaminase Adenosine deaminase derived from bovine intestineEnzyme replacement therapy for the treatment of severe combined immunodeficiency disease associated with adenosine deaminase deficiencyIncrease of circulation time and reduction of immunogenicityFDA 1990IMAdynovate?PEG-drug conjugateRecombinant antihemophilic factor Hemophilia AIncrease of the drug half life and stabilityFDA 2016IVAmBisome?LiposomeAmphotericin BSystemic fungal infections, cryptococcal meningitis and visceral leishmaniasisMPS targetingFDA 1997IVAmphotec?Colloidal dispersion of disc-like particles of amphotericin B and cholesteryl sulfateAmphotericin BInvasive aspergillosis in patients with kidney problems or unresponsive to conventional therapyMPS targetingFDA 1996IVCimzia?PEGylated antibodyFab fragment of a humanized anti-TNF-alpha antibodyRheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderate-to-severe plaque psoriasis, Crohns diseaseIncrease of circulation time and reduction of.