Biotin conjugates in targeted drug delivery: is it mediated by a biotin transporter, a yet to be identified receptor, or (an)other unknown mechanism(s)?

-biotin competition experiments conclude with the presence of a free carboxylic acid being essential for its uptake via the sodium-dependent multivitamin transporter (SMVT, the major biotin transporter). However, biotin conjugation with a payload requires modification of the carboxylic acid to an amide or ester group. Then, there is the question as to how/whether the uptake of biotin conjugates goes through the SMVT. If not, then what is the mechanism? Herein, we present known uptake mechanisms of biotin and its applications reported in the literature. We also critically analyse possible uptake mechanism(s) of biotin conjugates to address the disconnect between the results from SMVT-based SAR and "biotin-facilitated" targeted drug delivery. We believe understanding the uptake mechanism of biotin conjugates is critical for their future applications and further development.