The steroid hormone receptors (SHRs) among nuclear hormone receptors (NHRs) are steroid ligand-dependent transcription factors that play important roles in the regulation of transcription of genes promoted via hormone responsive elements in our genome. Aberrant expression patterns and contextspecific regulation of these receptors in cancer, have been routinely reported by multiple research groups. These gave an window of opportunity to target those receptors in the context of developing novel, targeted anticancer therapeutics. Besides the development of a plethora of SHR-targeting synthetic ligands and the availability of their natural, hormonal ligands, development of many SHR-targeted, anticancer nano-delivery systems and theranostics, especially based on small molecules, have been reported. It is intriguing to realize that these cytoplasmic receptors have become a hot target for cancer selective delivery. This is in spite of the fact that these receptors do not fall in the category of conventional, targetable cell surface bound or transmembrane receptors that enjoy over-expression status. Glucocorticoid receptor (GR) is one such exciting SHR that in spite of it being expressed ubiquitously in all cells, we discovered it to behave differently in cancer cells, thus making it a truly druggable target for treating cancer. This review selectively accumulates the knowledge generated in the field of SHR-targeting as a major focus for cancer treatment with various anticancer small molecules and nanotherapeutics on progesterone receptor, mineralocorticoid receptor, and androgen receptor while selectively emphasizing on GR and estrogen receptor. This review also briefly highlights lipid-modification strategy to convert ligands into SHRtargeted cancer nanotherapeutics.

The benzimidazole-1,2,3-triazole hybrid 4f selectively interacted with G-quadruplex DNA over duplex DNA, inhibits cell cycle at the G2/M phase, inducing apoptosis, and may be a G-quadruplex DNA groove binder with anticancer activity.

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Targeted delivery of therapeutics such as small molecule drugs or nucleic acids exclusively to the nucleus of diseased mammalian cells poses a significant challenge. The development of targeting ligands that can specifically enter certain cancer cells via a specific receptor-mediated endocytosis and then traffic exclusively to the nucleus to deliver the cargo inside it can achieve this goal. We have developed an end-functionalized shikimoylated-polypeptide with pendant shikimoyl moieties that can enter mammalian cells via the mannose receptors and are then exclusively trafficked into the nucleus. The presence of the shikimoyl group in the polypeptide, which traffics it exclusively to the nucleus, contrasts with the mannosylated or galactosylated glycopolypeptides that are distributed all over the cytoplasm or the mannose-6-phosphate containing polypeptide that is exclusively trafficked to the lysosome. Using challenge experiments, we demonstrate that these polypeptides can enter both dendritic and cancer cells through mannose-receptors and subsequently enter the cell nucleus via the interaction with a nuclear pore complex (NPC) protein importin-α/β1. To the best of our knowledge, this represents the first example of a synthetic polyvalent glycopolypeptide mimic that performs the dual function of entering mammalian cells through specific receptors and subsequently traffics into the nucleus. The conjugation of these end-functionalized shikimoylatedpolypeptides to other biological entities, such as recombinant anticancer drugs, DNA, RNA, and CRISPR-Cas9, may be a suitable alternative for delivery of these biological entities into cells affected by cancer and other genetic diseases.

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