Compared with other immune cells, most of which preferentially migrate to lymphoid organs or livers, MDSCs show more specific tumor tropism ( Eisenstein et al., 2013).

It has been reported that a large number of MDSCs are recruited to the tumor tissue and pre-metastatic niches during tumor expansion ( Bosiljcic et al., 2019 Hoffmann et al., 2019 Cassetta et al., 2020). They play a critical role in tumor progression and metastasis ( Tian et al., 2019 Swierczak and Pollard, 2020), and are correlated with poor prognosis ( Zhang et al., 2017).

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that constitutes an important part of the immunosuppressive tumor microenvironment ( Veglia et al., 2018). However, in order to achieve a high targeting efficiency, it is essential to have a reagent with high binding affinity and specificity to the carrier cell that allows for effective drug internalization in circulation. In this regard, a direct in situ loading strategy provides a better alternative ( Feng et al., 2020). However, viability and migration property of the cells can be altered during the drug-loading process in addition, cell manipulation is a costly and sophisticated process ( Dekaban et al., 2013). Most studies on cell-mediated drug delivery have mainly focused on packaging carrier cells with a therapeutic cargo ex vivo ( Timin et al., 2018 Tang et al., 2021). Indeed, many immune cells including T cells, monocytes and neutrophils, macrophages have all been tested as the vehicle for tumor-targeted drug delivery ( Nakamizo et al., 2005 Huang et al., 2015 Xia et al., 2020 Ye et al., 2020 Qu et al., 2021). Various tumor-associated cell types can serve as the vehicle for cell-based drug delivery making the best use of their natural tendency on tumor homing in response to tumor-secreted chemoattractants ( Tang et al., 2021). Cell-based drug delivery is believed to possess a number of advantages over the conventional drug delivery approaches, such as active delivery with high selectivity, prolonged retention, and sustained drug molecule release ( Su et al., 2015 Huang et al., 2018 Zhang et al., 2021). With this promising approach, adequate cells can serve as a carrier to drive therapeutic agents deep into the tumor ( Combes et al., 2020). Cell-mediated drug delivery is one of such options ( Xue et al., 2017 Kutova et al., 2019). Thus, there is a high demand for developing new drug formulations and identifying new delivery routes that facilitate tumor enrichment and intratumor penetration of anti-cancer therapies ( Chen et al., 2017 Li et al., 2020). Multiple physical and biological barriers block drug molecule penetration in the tumor tissue, rendering most therapeutic agents ineffective ( Blanco et al., 2015 Rosenblum et al., 2018). Taken together, we have identified a new reagent for enhanced tumor-targeted drug delivery. In addition, M1 can penetrate into the tumor tissue more effectively by hitchhiking on MDSCs. In the process, we have identified a sequence-modified aptamer (M1) that shows an enhanced binding affinity to MDSCs over the parental T1 aptamer. In the current study, we have carried out structure-activity relationship analysis to further optimize the aptamer. We recently identified a DNA-based thioaptamer (T1) with tumor accumulating activity, demonstrated its potential on tumor targeting and drug delivery. Since they constantly infiltrate into the tumor tissue, these cells are considered as an ideal carrier for tumor-targeted drug delivery. Myeloid-derived suppressor cells (MDSCs) play a critical role in tumor growth and metastasis. 3Weill Cornell Medical College, White Plains, NY, United States.2Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, China.

1Department of Nanomedicine, Houston Methodist Academic Institute, Houston, TX, United States.

Shaohui Tian 1,2, Thomas Welte 1, Junhua Mai 1, Yongbin Liu 1, Maricela Ramirez 1 and Haifa Shen 1,3*

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