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Page 20 of 26 Yang et al. Soft Sci 2024;4:9 https://dx.doi.org/10.20517/ss.2023.43

the impact of macrophages on immune response by inhibiting the production of inflammatory
[114]
mediators . Inversely, gallium could upregulate anti-inflammatory cytokines, such as IL-10, which is of
[115]
great significance in inflammation resolution [Figure 6E] . Besides, the function of lymphocytes is also
modulated by transferrin-gallium complexes that restrain the lymphocyte proliferation and
immunoglobulin production greatly . Chang et al. demonstrated that with a certain concentration of
[116]
gallium treatment (1-10 µg/ml), peripheral blood mononuclear cells would be arrested in the S phase of the
cell cycle .
[117]

Iron is one of the most important elements for almost all cells because of its indispensable role in a large
number of Fe-dependent enzymes and proteins. Its significance lies in its essential contribution to cell
survival, proliferation, and differentiation. Iron deficiency can induce anemia, while excessive iron is
responsible for ferroptosis due to the overproduction of superoxide and hydroxyl radicals. Thus, the iron
homeostasis is a delicate balance between import, storage, utilization, and export [103,118] . As mentioned above,
3+
the application of Ga may interfere with the Fe-dependent physiological function and trigger unexpected
negative effects. However, Zhang et al. discovered a unique anti-inflammatory pathway by gallium
3+
3+
nanodroplets (GNDs) independent of Ga -Fe competitive binding. Different from the Ga nonspecific
3+
anti-inflammatory mediator inhibition, which is harmful to the cellular iron homeostasis, GNDs can
upregulate eIF2α phosphorylation. This specific action disturbs the synthesis of inducible nitric oxide so that
[119]
none of the activated macrophages showed any sign of iron homeostasis interference .
LM-mediated graft rejection relief
Organ transplantation is a historic progress in human medicine and health development, and it is the only
effective method for the treatment of a great deal of end-stage diseases. Nowadays, the demand for organ
transplantation is still unmet. Cryopreservation is acknowledged as a way to significantly extend the
preservation time of isolated organs, which greatly alleviates the current contradiction between organ
supply and demand. Beyond that, however, organ transplantation remains confronted with grim challenges.
Many recipients are tortured by the serious immune rejection after receiving the transplanted organ,
resulting in dysfunction of the graft, and acute immune reaction is even life-threatening. Therefore,
immunosuppressants were introduced to alleviate the immune responses, which effectively improved the
[120]
transplant prognosis .

As mentioned above, gallium is thought to be an immunomodulating agent in relieving inflammatory
responses, particularly the immune process mediated by T cells and macrophages. Its unique property
intrigues researchers, prompting an investigation into whether gallium could act as a metal ion
immunosuppressant to attenuate immunological rejection after transplantation. Orosz et al. applied gallium
to suppress the rejection in a cardiac allograft transplantation mouse model, indicating that the survival of
mice was significantly improved . Meanwhile, histological tests showed mitigated immune rejection. The
[121]
other independent experiment also confirmed the immunomodulating potential of gallium in
transplantation .
[122]
Therefore, it is reasonable to further speculate that gallium can be applied as a unique metallic substance
added to CPAs before cryopreservation. When the organ is transplanted into the recipient, gallium at
millimole levels can rapidly affect the immune system, avoiding both violent inflammatory responses and
grievous immune rejection, which are fundamentally dependent on the immunomodulatory effects of
gallium on T cells and macrophages [Figure 6F]. In addition, a substantial body of literature has also
claimed that gallium is a potent antibacterial substance compared with traditional antibiotics in that
pathogens have already become highly resistant to abused antibiotics, such as penicillin, whereas no drug