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Yang et al. Soft Sci 2024;4:9 https://dx.doi.org/10.20517/ss.2023.43 Page 15 of 26

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spiny deformations to cause mechanical damage to the surrounding ice within only 1 ms , as shown in
Figure 5C i. The deformation ratio of LMMPs is determined by the properties of the surrounding solution
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[Figure 5C ii] . In this way, an enhanced cryoablation efficiency would be realized by simply employing
LMMPs as cryosurgery agents. Sun et al. exerted cryoablation to C8161 tumors in a nude mice model, and
as shown in Figure 5C iii, they demonstrated improved tumor elimination efficiency and a higher survival
[85]
rate in the LMMP injection group .
In order to increase the targeting ability and increase the destructive efficacy, Wang et al. assembled cell
membrane-encapsulated Ga particles (Ga/MPs) with the ability to be delivered into cancer cells to exert
cactus-like deformation inside endosomes under freezing to achieve endosomal escape [Figure 5D i and ii].
[91]
They demonstrated the prominent targeting capability of Ga/MPs through fluorescent staining tracing
methods. The fluorescence microscopy images show co-localization of endosomes and Ga/MPs. After
freezing treatment, the co-localization area significantly decreased, indicating more endosomal escape
caused by Ga/MPs. With the injection of Ga/MPs, the cryosurgery efficiently inhibited tumor growth
compared with the outcome of the group without cryosurgery. In addition, without membrane
encapsulation, the cryosurgery inhibited tumor growth with a slighter effect compared to the Ga/MPs
combined cryosurgery group. Such a distinct comparison verified the enhanced anti-tumor effect deriving
from Ga particle deformation. To further improve the therapy effect, combined chemotherapy was made by
loading anti-tumor drugs with Ga/MPs and realized a better tumor elimination effect [Figure 5D iii].

These works indicated that LMs, with various forms, could be employed as synergistic platforms to exert
multi-mode tumor therapy, especially to enhance cryoablation efficiency.

PROSPECTS OF LM IN CRYOBIOLOGY
LM-mediated cryosurgery
As mentioned above, cryosurgery attracts increasing attention based on the characteristics of minimally
invasive and lower side effects than traditional surgical treatment. By focusing on the key points during the
operation, LMs have been applied to enhance the biological heat transfer successfully, therefore achieving
sufficient freezing to target tumors and showing great potency in the animal model of melanoma. It has
been reported that LMs can act as an extraordinary contrast agent for X-ray visualization; thus, it is
promising to realize accurate cryosurgical guidance through solid tumor vascular network injection of LMs.
Moreover, LMs are also prospective in synergistic immunotherapy and direct tumor killing by iron
deprivation to boost tumor treatment efficiency when combined with cryosurgery, all of which will be
discussed in detail below.

LM-mediated tumor imaging optimization
Medical imaging refers to the technology of obtaining non-invasive images of internal tissues of the human
body or part of the body for medical treatment or research. Since Roentgen discovered X-rays in 1895,
imaging has been one of the most critical parts of clinical trials, which plays an important role in diagnosing
and preoperatively planning diseases that cannot be directly observed. Tumors are highly heterogeneous
with irregular shapes and are normally deeply embedded in tissues. Thus, these intrinsic properties of
tumors pose a serious challenge to surgical methods, including cryosurgery, which relies on physical
elimination of tumor tissues. Meanwhile, inaccurate imaging guidance can easily lead to uncontrolled cold
release and cause damage to adjacent healthy tissue.

At present, most cryosurgeries are percutaneous ablation guided by CT or ultrasound, which are widely
used because of their simplicity and low cost . However, these two imaging methods still have
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