Review For reprint orders, please contact: reprints@futuremedicine.com Ligand decorated chitosan as an advanced nanocarrier for targeted delivery: a critical review Maimoona Qindeel 1 , Naveed Ahmed 1 , Gul M Khan 1 & Asim U Rehman* ,1 1 Department of Pharmacy, Quaid-i-Azam University, Islamabad 45320, Pakistan *Author for correspondence: arehman@qau.edu.pk Nontargeted delivery systems present nonspecifc delivery, low transfection effciency and high toxicity. Ligand-conjugated chitosan (CS) nanocarriers have emerged as an outstanding option for achieving ac- tive delivery specifcally and preferentially to the target sites by exploiting receptors mediated endocy- tosis. Mannosylated CS nanocarriers have brought tremendous breakthrough in gene therapy and have proven to be an excellent choice for treatment of infectious and infammatory diseases. Similarly, folate and antibodies-conjugated CS play a signifcant role in diagnosis and treatment of various cancers. Cur- rent evidences obviously propose ligand-decorated CS as an attractive option for diagnosis and treatment of dreadful conditions. In order to bring huge revolution in the feld of targeted delivery, challenges associated with these nanocarriers needs to be addressed. First draft submitted: 16 December 2018; Accepted for publication: 20 February 2019; Published online: 5 June 2019 Keywords: chitosan • diagnosis • endocytosis • ligand • receptors • targeted delivery • therapeutic applications The paradigm of drug delivery is changing; researchers are progressively going beyond the approach of conventional and nontargeted systems towards a new era of targeted drug delivery. Conventional and nontargeted delivery systems are allied with a number of problems [1]. For example, in gene therapy the most important challenge is engineering a safe and effective delivery vector. Approximately 70% of clinical trials are carried out on viral vectors such as adenovirus, adeno-associated virus and lenti virus. Even though, these vectors have significantly advanced the field but still several problems are associated with them including immunogenicity, carcinogenicity, broad tropism, limited DNA loading capacity and difficulty of vector production [2]. Other problems associated with conventional delivery systems is inefficient detection and treatment of a variety of disease conditions such as cancer, which is considered as a leading cause of death all over the world. In solid tumors, after initial removal of cancer cells, remnant cells are managed with chemotherapy. However, toxicity and nonselective delivery of therapeutic agents are the major concerns allied with conventional chemotherapy [3]. Additionally, the delivery of proteins is very challenging, as these molecules are very liable to enzymatic degradation and unable to cross the cell membrane to reach their target site. Consequently, there is a need to design such nanocarriers that can deliver active moieties specifically and preferentially to the target sites while minimizing off target delivery. In order to overcome the aforementioned problems, the concept of active targeted delivery system was introduced. Active targeting refers to incorporation of high affinity ligands on the surface of nanocarriers to facilitate precise homing, higher retention and uptake by target cells. Ligands are basically molecular extensions that decides the fate of the delivery system for active targeting and gets an overall higher therapeutic response. These ligands are very specific in binding with clustered receptors that are remarkably overexpressed at pathological tissues and cell surfaces. Now receptor-mediated targeting systems have become an auspicious approach for targeted delivery at a cellular level [4]. A huge number of surface-tailored polymers are used for the fabrication of active targeted delivery systems such as polyethylene glycol (PEG), polylactic co-glycolic acid (PLGA), polylactic acid (PLA), pectin, chitosan (CS) and many more. CS has emerged as a novel class of polymers that shows highly refined functions owing to its unique biological activity, outstanding biocompatibility, nonimmunogenicity, nontoxicity, noncarcinogenicity and complete biodegradability. CS being a natural polymer possesses additional distinctive properties that make it Nanomedicine (Lond.) (Epub ahead of print) ISSN 1743-5889 10.2217/nnm-2018-0490 C  2019 Future Medicine Ltd