br Implications of all the available

Implications of all the available evidence
Our study suggests targeted, combined therapies targeting both cancer and the tumour niche can potentially be safer and more ef-fective to treat bone metastases than monotherapies and non-targeted treatments (e.g. chemotherapies). This platform technol-ogy is modular and could be applied to other types of tumours or diseases that require delivery of multiple cargos. Moving towards clinical studies, future work should systematically study the dos-age, number, frequency and schedules of treatments, potentially together with patient stratification based on disease stages, in order to obtain optimal therapeutic outcomes especially in the long-term. Furthermore, an optimal therapeutic schedule should be identified (sequential injections, repeated treatments and mixing of MSC engineered differently).
median-survival of 19–25 months, along with severe morbidities includ-ing intractable pain, pathological fractures, spinal cord compression, and hypercalcemia [2]. Breast cancer Haloperidol alter the bone microenvironment and produce factors to promote osteoclastogenesis. In turn, bone resorp-tion by osteoclasts releases growth factors, which stimulate tumour pro-gression [3]. The reciprocal interaction between breast cancer cells and the bone microenvironment, called the “vicious cycle,” accelerates tu-mour growth and bone destruction. An effective therapy to treat bone metastasis, therefore, would require efficient targeting of both the cancer cells and their microenvironment. Such a treatment has been lacking. In fact, despite major progress in cancer therapies, the 5-year relative sur-vival rate for metastatic breast cancer has barely improved over the past 20 years, remaining around 20% [2,4]. Common treatments including surgery, chemotherapy, radiation therapy, and endocrine therapy are only palliative and are often associated with significant systemic toxicity 
[5]. Standard of care drugs targeting bone resorption, including bisphosphonates and Denosumab (antibody targeting the receptor acti-vator of NF-κB ligand, RANKL), which act by inhibiting osteoclastogenesis through different mechanisms, are controversial in their anti-tumour mechanisms [6,7]. Most importantly, these therapies, alone or in combi-nation, are ineffective in targeting both tumour growth and osteolysis, often leading to relapse, new metastasis, drug resistance, and notably, high systemic toxicity [8]. In addition, targeted drug delivery systems for bone metastasis, especially those using nanoparticles, are still in their infancy [9–13], and typically suffer from rapid clearance, poor targeting efficiency, and inability to penetrate to the centre of large and poorly vascularised metastatic tumours [14].
Here we exploit a stem cell based approach for targeted delivery of a combination of therapeutics, which interrogates both the cancer and its niche. Stem cells, including mesenchymal stem (or stromal) cells (MSC), act as potent, autonomous, and adaptive agents [15,16], and have recently been tested as vehicles for drug delivery in cancer [17–22], including in clinical trials [23]. Specifically, using a facile mRNA-engineering approach, we programmed mesenchymal stem cells with machinery to enable a) specific and efficient bone metastasis homing through engineered P-selectin glycoprotein ligand-1 (PSGL-1) and Sialyl-Lewis X (SLEX), which target highly expressed selectins in vessels surrounding the tumour [24–26], b) local cancer killing through the cytosine deaminase (CD)/pro-drug 5-Fluorocytosine (5-FC) system [27], and c) osteolysis inhibition within the tumour niche through ex-pression of modified osteoprotegerin (OPG) [28], a natural decoy recep-tor for RANKL, a key mediator in tumour-induced osteoclastogenesis (Fig. 1). Previous studies targeting bone tumours through a cell-based therapy approach used genetically modified cells to only deliver a single therapeutic molecule [29–31]. Engineering cells with mRNA-based pro-tein expression is advantageous for targeting bone metastasis due to its simplicity, safety (no genetic engineering), transient and rapid protein translation after transfection, and ability to express multiple factors si-multaneously for combinatorial treatment [32–34]. In this report, using a xenograft intratibial model and a syngeneic model of spontane-ous bone metastasis, we demonstrated that MSC engineered to simulta-neously express PSGL-1/SLEX, CD, and OPG exhibit enhanced homing to the bone metastatic niche where they effectively kill tumour cells and preserve bone integrity with minimal toxicity.