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Du et al. Soft Sci 2024;4:35 https://dx.doi.org/10.20517/ss.2024.31 Page 15 of 23

local tumor treatment and reduce drug toxicity to normal tissues. Achieving long-term, controllable, and
sufficient drug delivery is crucial in this method.

Ahsan et al. developed a temperature-responsive injectable hydrogel for the effective and continuous
[91]
delivery of the anticancer drug disulfiram (DSF) to cancer cells [Figure 5A]. The hydrogel has excellent
biocompatibility, with liquid injection at room temperature (25 °C) and rapid gel formation at body
temperature (36.5 °C). The hydrogel relies on swelling for movement. Experiments showed that the
hydrogel expanded most at 37 °C and pH 1.2, and less at 25 °C and pH 7.4, indicating that the drug can be
rapidly released under acidic conditions and high temperatures. This confirms that DSF can be effectively
delivered under physiological conditions.

[102]
Hu et al. synthesized a pH-sensitive carboxymethyl chitosan (CMCS) hydrogel through acid bonding
[Figure 5B]. Using doxorubicin (DOX) as a model drug, the hydrogel can be implanted at the tumor site in
any shape. The hydrogel controls the release of the drug in response to pH levels. Within 144 hours, the
hydrogel released only 29.9% of DOX at pH 7.4, while the cumulative release reached 49.3% and 65% at pH
5.0 and 6.5, respectively. In vivo studies showed that the implanted hydrogel significantly prolonged the
release time of DOX and increased drug accumulation in the tumor area. Continuous drug release in the
weakly acidic environment of tumor tissue effectively controlled tumor metastasis and inhibited tumor
growth.

Gangrade et al. developed a self-repairing hydrogel that exhibits volume shrinkage under NIR laser
[103]
irradiation, allowing for non-invasive administration of DOX to tumors [Figure 5C]. After NIR
radiation, the synergy between the locally induced high temperature by NPs and the DOX released by
hydrogel contraction effectively kills tumor cells.

In future studies, multiple stimulus-responsive methods can be combined to achieve a synergistic effect in
tumor treatment while further reducing side effects on surrounding healthy tissues.

Diabetes mellitus
Diabetes mellitus, a widespread global disease, poses a serious threat to public health. Individuals with
diabetes require daily insulin injections to maintain normal blood glucose levels. However, frequent post-
meal insulin injections not only diminish the patient's quality of life but also fail to dynamically adjust the
[121]
insulin dose and timing, leading to unnecessary side effects . Furthermore, poor blood sugar control can
result in severe complications. Glucose-responsive hydrogel actuators can undergo subtle conformational
changes in response to glucose, thereby promoting the precise release of insulin .
[104]

Ye et al. developed glucose-responsive hydrogels that undergo reversible rapid volume phase transitions in
response to fluctuations in blood glucose concentration, with the potential to simulate pancreatic activity
[105]
for regulating insulin delivery [Figure 5D]. Hydrogels can control the rate of insulin release by adjusting
the size of the gel network. When glucose is added in the range of 50.0 µM to 20.0 mM, the nanogel can
expand and stabilize in less than one second. The insulin release rate may increase tenfold when
transitioning from normal glucose levels (6.0 mM) to elevated glucose levels (15.0 mM). This self-regulating
insulin delivery characteristic significantly enhances the efficacy of diabetes treatment.

[104]
Lee et al. synthesized a glucose-responsive hydrogel based on trehalose polymers for insulin delivery
[Figure 5E]. Hydrogels prepared from trehalose polymers and boric acid crosslinking agents can release
insulin in a glucose-responsive manner. The two main mechanisms of insulin release by borate hydrogel are