Review on Engineered stem cell-based strategies

Stem cells have been perceived as the cornerstone of regenerative medicine due to their
remarkable properties, holding promise for addressing a multitude of debilitating conditions.
However, the transition from stem cell research to effective therapeutics was not as effective due
to compatibility issues and the intricate microenvironmental nuances within the body. These
challenges underscore the need for innovative strategies to optimize the properties of stem cells
for therapeutics. In response, the paper provides the new avenues in engineered stem cell-based
strategies aimed at eliciting precise and optimal responses within the body. Specifically,
engineered stem cell-based strategies provided strategies regarding targeted delivery, degradation
of reactive oxygen species (ROS), drug toxicity attenuation, drug loading capacity augmentation,
and minimization of immune responses. These engineered stem cell-based techniques, includes
genetically engineered stem cells, nanoparticle-internalized stem cells, nanoparticle-anchored
stem cells, and exosomes derived from stem cells that have achieved success in the field of stem
cell therapeutics and drug delivery systems.

Expanding on this, the evolution of stem cell therapy from the use of adult hematopoietic
stem cells (HSCs) to mesenchymal stem cells (MSCs) in treating various conditions marks a
significant advancement. Specifically, their availability and ease of expansion from diverse
sources such as bone marrow, umbilical cord, and adipose tissue, MSCs have paved the way for
clinical translation. Similarly, pluripotent stem cells (PSCs) therapy, encompassing embryonic
stem cells and induced PSCs (iPSCs), represents a second generation in stem cell treatment.
Despite the global launch of over 40 types of stem cell drugs, concerns persist regarding their
safety, particularly immune rejection. Efforts to mitigate these concerns have led researchers to
explore autologous iPSCs, though challenges in immune evasion persist. Stem cell therapeutics
have showcased significant advantages in treating conditions like anemia and Crohn's disease,
fueling extensive clinical trials to explore their efficacy across diseases ranging from diabetes to
osteoarthritis. Therefore, engineered stem cells mention in the paper provides a new avenue of
augmenting treatment efficiency and expanding clinical applications by addressing challenges
such as toxicity and enhancing cellular functions in vivo. However, persistent challenges,
including stem cell vulnerability to the microenvironment, exacerbation of disease progression,
and mechanical forces impacting differentiation and self-renewal potential.
 First, genetically engineered stem cells achieved enhanced therapeutic potential through
alterations in protein expression on cell membranes, enabling them to withstand adverse
environmental conditions and optimize therapeutic outcomes. This adaptability has led to FDA
approval for genetically engineered stem cell therapies, highlighting their efficacy in addressing
diseases related to chromosomal anomalies and providing sustained therapeutic benefits. For
instance, in Alzheimer's disease treatment, genetically modified neural stem cells expressing Aβ-
degrading protease have shown promise by facilitating sustained degradation of harmful Aβ
within the brain. Consequently, this enhances the survivability of transplanted stem cells and
endogenous neurons, demonstrating the potential of genetically engineered stem cells to combat
neurodegenerative diseases effectively. Moreover, in cancer treatment, genetically engineered
stem cells have been utilized to suppress tumor formation and improve the survival rate of
tumor-bearing mice. By transducing mesenchymal stem cells with specific genes, researchers
have observed inhibition of tumor nodules formation, reduction in immunosuppressive cells
frequency, and enhanced survivability of tumor-bearing mice. Additionally, genetically
engineered stem cells have been employed for gene delivery purposes, enhancing the
effectiveness of radiotherapy in hepatic tumors by transporting the sodium iodide symporter
gene, thus increasing iodine absorption by tumor cells.

Second, nanoparticle-internalized stem cells leverage nanoparticles to regulate stem cell

activities, resist inflammatory environments, and control behavior externally. As a result, this
modification leads to enhanced resilience in adverse environments, increased resistance to
Reactive Oxygen Species (ROS), and broadening the scope of disease treatment, diagnosis, and
pathological mechanism exploration. Specifically, the ROS resistance is attribute to the
utilization of such as manganese-doped metal oxides and cerium oxide nanoparticles, which offer
effective ROS scavenging capabilities, to shield stem cells from oxidative stress and restoring
their compromised functionality. For instance, the incorporation of nanocomposites like ROS-
sensitive dextran derivatives with copper-based nanozymes and gold nanoparticles enables stem
cells to not only respond to intracellular ROS stimulation but also provides them with in vivo
tracking capabilities. Furthermore, in the realm of tumor therapies, stem cells loaded with
nanoparticles demonstrate an active targeting mechanism towards tumor sites, significantly
enhancing drug delivery efficiency while simultaneously reducing systemic toxicity. This
strategy involves encapsulating chemotherapeutic drugs or prodrugs within nanoparticles, which,
when combined with stem cells, result in improved tumor suppression effects at reduced drug
dosages. Additionally, the integration of stem cells with light-responsive nanoparticles facilitates
the in vivo tracking of stem cell fate and enables the evaluation of their behavior in response to
various stimuli, thereby aiding in the development of targeted therapeutic interventions.

Third, Nanoparticle-anchored stem cells involve attaching nanoparticles to the stem cell
membrane through surface connections, thereby enhancing drug loading capacity and improving
drug delivery efficiency. As a result, this technique circumvents issues like toxicity problems
associated with drug leakage and intracellular degradation of inorganic materials, offering a more
precise and timed release of nanoparticles. Moreover, given the properties of this derivative, it is
applied in managing idiopathic pulmonary fibrosis by targeting specific cells and enhancing drug
loading capacity. Additionally, this method facilitates the tracing of stem cell fate through in vivo
imaging techniques like CT imaging.

Lastly, exosomes derived from stem cells are nanoscale extracellular vesicles enriched
with diverse cargoes, including proteins and RNA. In turn, stem cell exosomes offer distinct
advantages over their parent cells, such as enhanced ease of storage, transport, and a reduced risk
of adverse effects. Additionally, these exosomes can be efficiently obtained through various
methods, including stem cell culture, and are amenable to scaling up for large-scale production.
This scalability underscores their potential for widespread application in cell-free therapy and
presents promising avenues for future research and clinical use. Nevertheless, challenges persist,
notably the need for standardized isolation protocols and rigorous quality control measures.
Despite these challenges, stem cell-derived exosomes have shown promising outcomes in
specific applications. For instance, they have demonstrated the ability to achieve long-term
residence in the uterine cavity and aid in the restoration of damaged endometrium. Furthermore,
in preclinical models, these exosomes have exhibited notable tissue repair capabilities across
various conditions, such as acute myocardial infarction, osteoarthritis, and rotator cuff tendon
injury. Moreover, observations of mesenchymal stem cell (MSC)-derived exosomes regulating
key gene expressions, such as down-regulating p53 and up-regulating cyclins, highlight their
potential in facilitating repair processes following acute kidney injury.

In summary, the engineered stem cell-based strategy provides additional tool for
therapeutics, targeted medication, cancer treatment strategies and monitoring systems. First,
genetically modified stem cells demonstrated enhanced therapeutic potential in combating
various diseases, including neurodegenerative disorders and cancer. Second, the utilization of
nanoparticles to internalize stem cells further augments their resilience in adverse environments
and broadens their applicability in disease treatment and diagnosis. Third, nanoparticle-anchored
stem cells provide a promising avenue for improving drug delivery efficiency and precision. And
lastly, the emergence of exosomes derived from stem cells offers a cell-free therapeutic approach
with advantages in storage, transport, and reduced adverse effects. Despite the challenges
associated with standardization and quality control, stem cell-derived exosomes have shown
promising outcomes in tissue repair and regenerative medicine applications. Thereby, the
strategies revolutionize the landscape of regenerative medicine, offering personalized treatments
and improved patient outcomes.