Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue

Wang, Huawei; Alarcón, Christina N.; Liu, Bei; Watson, Felicia; Searles, Stephen; Lee, Calvin K.; Keys, Jeremy; Pi, Willie; Allen, D. J.; Lammerding, Jan; Bui, Jack D.; Klemke, Richard L.

doi:10.1038/s41551-021-00815-9

Cited by 58 publications

(53 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rather than delivering an mRNA cargo into targeted cells, this approach harnesses the cellular paracrine function to directly deliver proteins synthesized from mRNA introduced into cells ex vivo. It offers many advantages compared to synthetic LNPs, including biocompatibility, extended longevity in circulation and endogenous intracellular/ intercellular signaling 98,99 (Fig. 3c).…”

Section: Cell-based Packagingmentioning

confidence: 99%

Unlocking the promise of mRNA therapeutics

et al. 2022

View full text Add to dashboard Cite

z and enhanced catalysis to the ribosomal complex [32][33][34][35][36] . Optimization of the poly(A) tail length (100-300 nucleotides) has proven critical in balancing the synthetic capability of a given mRNA 34,36 . Similarly, improved 5′ cap analogs not only increase translational capacity but also enhance capping efficiency, from 70% to 95%, greatly improving the in vitro transcription process 32,37 . The composition of the 3′ and 5′ UTRs can also be customized for the target cell of interest, increasing the efficiency and tissue specificity of translation 35,38,39 .At present, most mRNA products contain a synthetic UTR sequence from α-globin or β-globin [38][39][40] , but UTR optimization can further improve protein expression by a few fold 41,42 . Careful screening and customization to the target of interest could conceivably offer a wide range of improvements in future UTR sequences, allowing each mRNA to be tailored to the targeted cell and disease-induced microenvironment to maximize protein synthesis per mRNA transcript [41][42][43][44] .Perhaps the most critical advances in mRNA vaccines and therapeutics lie in the discovery that the inclusion of chemically modified nucleosides, particularly in uridine moieties, can markedly increase protein expression after in vitro or in vivo transfection. The chemical modifications of most new RNA formulations to date have been central in intellectual property claims 45,46 . Thus far, over 130 different naturally occurring chemical modifications of RNA have been reported 47,48 . The interest in methylpseudouridine and other modified nucleosides centers on their capacity to greatly reduce (up to 100-fold) detection by the Toll-like receptors of the innate immune system, resulting in an increase in protein expression in vivo compared to unmodified mRNA 40,[49][50][51][52][53] . Combinations of different types of chemical modifications, carriers, for the treatment of chronic conditions. The fifth section provides a comprehensive table and summary of current clinical trends in mRNA therapeutics. Finally, the sixth section considers the scope of mRNA therapeutics and guiding principles for near-term and longer-term clinical development of this novel therapeutic modality.

show abstract

Section: Cell-based Packagingmentioning

confidence: 99%

Unlocking the promise of mRNA therapeutics

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Due to the unpredictable toxicity and poor scalability of nanocarriers in the human body ( 104 ), other advanced drug carriers have gradually attracted attention, such as hydrogels ( 105 ), exosomes ( 106 ), and enucleated cells ( 107 ). A Melittin-Rada32 hybrid peptide hydrogel loaded with doxorubicin (DOX) was designed to reshape the tumor immune microenvironment in the treatment of melanoma, which specifically consumes M2 TAMs and increases activated CTL infiltration ( 108 ).…”

Section: Modulation Of Tams To Elevate Anti-pd-1/pd-l1 Immunotherapymentioning

confidence: 99%

Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression

2022

Front. Immunol.

120

View full text Add to dashboard Cite

Anti-programmed cell death 1 (PD-1) or anti-PD-ligand (L) 1 drugs, as classic immune checkpoint inhibitors, are considered promising treatment strategies for tumors. In clinical practice, some cancer patients experience drug resistance and disease progression in the process of anti-PD-1/PD-L1 immunotherapy. Tumor-associated macrophages (TAMs) play key roles in regulating PD-1/PD-L1 immunosuppression by inhibiting the recruitment and function of T cells through cytokines, superficial immune checkpoint ligands, and exosomes. There are several therapies available to recover the anticancer efficacy of PD-1/PD-L1 inhibitors by targeting TAMs, including the inhibition of TAM differentiation and re-education of TAM activation. In this review, we will summarize the roles and mechanisms of TAMs in PD-1/PD-L1 blocker resistance. Furthermore, we will discuss the therapies that were designed to deplete TAMs, re-educate TAMs, and intervene with chemokines secreted by TAMs and exosomes from M1 macrophages, providing more potential options to improve the efficacy of PD-1/PD-L1 inhibitors.

show abstract

“…However, simple stem cell therapy has safety risks. The enucleated human mesenchymal stromal cells (Cargocytes) 53 created by Klemke et al solve the above two problems very well. Cargocytes are a novel biomimetic system that uses density gradient centrifugation to enucleate but retain intrinsic cellular functions.…”

Section: Cell Membrane Source and Its Application In Cancer Therapymentioning

confidence: 99%

“…64 Despite the technical challenges in EV separation and inefficiencies in therapeutic cargo loading, once these challenges are overcome, EVs will unlock their full potential in drug delivery applications. In addition, the Cargocyte delivery vehicle developed by Klemke et al 53 may also be a biomimetic carrier in the future.…”

Section: Prospects and Challengesmentioning

confidence: 99%

“…More importantly, even if the membrane integrity problem is solved in the cell membrane biomimetic system, traditional cell membrane-coated NPs have lost their original organelles and key cellular mechanisms, resulting in the inability to ''decipher'' key signals and chemical gradients required for chemical orientation, the disability to generate energy and activate high-affinity integrin-mediated endothelial adhesion, and being less able to generate propulsive forces to overflow the vasculature. 53 As a result, under the condition of ensuring application safety and controllability, a biomimetic system with cell communication functions that can regulate physiological and pathological processes and have certain chemotactic abilities to diseased tissues may be the biomimetic delivery vehicle of choice in the future. A good example is extracellular vesicles (EVs), which have developed rapidly over the past decade and play an important role in cellular communication, 62 in addition to their bilayer membrane properties for drug loading and NP coating.…”

Section: Prospects and Challengesmentioning

confidence: 99%

See 1 more Smart Citation