**1. Introduction**

Tuberculosis (TB) remains one of the most common human diseases today, causing nearly two million deaths per year [1]. One-third of the global population is estimated to be latently infected with *Mycobacterium tuberculosis*, which is attributed to the ability of the tubercle bacillus to remain dormant in its protective niche unrecognized by the host immune system [1–6]. In post-chemotherapy patients, the recurrence of TB is very common due to endogenous reactivation leading to death [5,7–10]. It is imperative to find strategies that could e ffectively target and facilitate dormant *Mycobacterium tuberculosis* (Mtb) clearance to avert disease reactivation and associated mortality.

CD271+bone marrow mesenchymal stem cells (BM-MSCs) serve as a novel host and a protective niche for non-replicating dormant *Mycobacterium tuberculosis* [11–14]. Mycobacterial bacilli remains intracellularly protected by standard anti-Tb drug treatment in mesenchymal stem cell populations, as shown in murine models and post-chemotherapy TB patients [11,13–15]. Das et al. demonstrated that in post-DOT (direct observed treatment) patients, a specific population of MSCs with CD271+ surface marker, harbor live nonreplicating Mtb bacilli [12]. The residual dormant Mtb population post-drug treatment may lead to endogenous reactivation and develop resistant forms [5,6,10,16–18]. We and others have shown that in murine models, prolonged anti-Tb drugs at standard dosages fail to clear the Mtb population inside CD271+BM-MSCs [13,14,19]. More importantly, despite 90 days of anti-Tb drug treatment in mice, CD271+BM-MSC-resident Mtb reactivates and leads to relapse [14]. We hypothesized that a BM-directed approach where anti-Tb drugs are delivered specifically to the bone microenvironment, can target Mtb inside BM-MSCs and reduce the relapse rate.

We and others have shown that generic nanoparticle formulations impart protection and provide countermeasures against various infections [20–26]. Currently, to reduce o ff-target toxicity and enhance e ffective tissue treatment, organ-homing nanoparticles (NPs) are being used as drug-delivery vehicles [27–31]. Among other NPs, liposomes are the most versatile and are widely used in clinical settings because of their biocompatibility and controlled release profile [21,27,30,32]. Recent studies show that the bone microenvironment could specifically uptake surface-modified liposomes and PLGA NPs (poly (lactic-co-glycolic acid)) compared to other organs [33–35]. Although for TB infections, tissue-specific liposomes have been reported previously [22,36–41], a novel approach of bone homing liposomes has not been addressed yet. In this study, we employed a biphosphate molecule, alendronate (Ald) as target moiety and PEG to formulated bone-homing liposomes in order to deliver the standard anti-Tb drugs rifampicin (RIF) and isoniazid (INH) right to the bone microenvironment. We propose that drug encapsulated bone-homing PEGylated liposome (BTL) nanoparticles can clear the Mtb bacilli residing in CD271+BM-MSCs and reduce the relapse rate.
