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Factors like unreliable and poor oral absorption, including an active Pgp-efflux point towards a compromised oral bioavailability (BA) of streptomycin sulfate (STRS). Latter instigates its parenteral use (i.m.) only. Furthermore, its chronic use leads to serious side effects like nephrotoxicity and ototoxicity. In the present study, we propose to develop streptomycin sulfate (STRS) loaded solid lipid nanoparticles (STRS-SLNs) for non-invasive intranasal (IN) delivery. STRS-SLNs were prepared using patented nanocolloidal aqueous dispersion technique (Indian Patent application 3093/DEL/2012). Small particle size (140.1 ± 7.0 nm) and significant entrapment efficiency (54.83 ± 2.1%) was achieved. Biodistribution studies using 99mTc showed a 3.15 and 11.0 times higher concentrations in the brain and blood of mice, respectively, on IN administration of STRS-SLNs in comparison to free (F)-STRS. Lower concentrations (3.3 times) in kidneys implicate lower nephrotoxicity. Similarly a 12 and 4 times lower levels of drug in liver and spleen, respectively upon administration of STRS-SLNs as compared to F-STRS also indicate its lesser accumulation in these reticuloendothelial system organs. Lipophillic enclosure imparted to STRS, coupled with small particle size, and its purported ability to inhibit Pgp-efflux due to the presence of tween 80, is considered to be responsible for a better BA shown by STRS upon incorporation into SLNs. This is predicted to result in an effective treatment of all types of tuberculosis including cerebral tuberculosis as indicated by high relative distribution to brain in comparison to free-STRS.