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Sun et al. Chem Synth 2023;3:16 https://dx.doi.org/10.20517/cs.2022.45 Page 11 of 17

inhibition of tumor growth.

Besides the high temperature triggered drug release, tumor microenvironment-induced controllable drug
[68]
release was designed for chemo-photothermal therapy as well. Zhao et al. synthesized CD-modified HA .
In the presence of CPT-modified Ada derivative, the host-guest interaction between CD and Ada promoted
the formation of supramolecular nanoparticles [Figure 5B]. With the loading of NIR absorptive dye, IR825,
the host-guest assemblies can cause a temperature increase of 40 °C upon laser irradiation, confirming their
excellent photothermal performance. In addition, the anticancer drug, CPT, was deliberately linked with
Ada by a disulfide bond, which can be cleaved by the concentrated GSH in tumor microenvironment.
Evidence showed that the combination of chemo and photothermal therapy ensured the efficient inhibition
of tumor growth.

Photodynamic-photothermal therapy
Photodynamic therapy is an emerging tumor treatment that uses light along with photosensitizer, which can
1
transfer laser energy to the surrounding oxygen, and produce reactive oxygen species (e.g., O ) [9,69] . The
2
combination of both photothermal therapy and photodynamic therapy will undoubtedly improve cancer
curative effects. One of the common strategies for constructing photodynamic-photothermal agents is to
encapsulate photosensitizers into photothermal agents utilizing host-guest interaction. Yang et al. fabricated
mesoporous silica-coated Au nanorods through a seed-induced growth method , which exhibited
[70]
relatively high photothermal conversion efficiency and can be employed for photothermal therapy
[Figure 6A]. Taking advantage of the Au surface, HS-modified -CD was covalently linked. Via host-guest
interaction, 5,10,15,20-Tetrakis (4-sulfonatophenyl)-porphyrin (TPPS4) coordinated with Gd , which acted
3+
as a photosensitizer, was encapsulated into the nanocomposite, resulting the obtainment of MSNR@Au-
TPPS (Gd). With 808 nm laser irradiation, the MSNR@Au-TPPS (Gd) showed excellent photothermal
4
4
behavior. While upon the irradiation of 660 nm laser, O was generated as well. With the combination of
1
2
the dual methodologies, the improved therapeutic effect was confirmed by in vivo experiments. This
principle was further expanded by Tang et al. [Figure 6B] . In their case, TTPY-Py, an AIE-active
[71]
photosensitizer, was incorporated into WP5-modified Au nanorods via host-guest interaction. Taking
TTPY-Py as a photosensitizer for the generation of reactive oxygen species and Au nanorods as
photothermal agents, the combination of photodynamic and photothermal synergistic therapy was realized
and an enhanced anti-tumor effect was achieved.

Other photothermal-based synergistic therapies
The incorporation of therapeutic genes with photothermal species leads to the construction of gene-
photothermal agents. Yue et al. prepared CB[7]-capped AuNRs, Ada-PEG and Ada-PLA (polylactic acid)
[Figure 7A]. When mixed together, the host-guest interaction between CB[7] and Ada occurred. Further
assisted with the hydrophobic (PLA) and hydrophilic (PEG) ligands, supramolecular vesicles (Au NVs) with
[72]
densely arranged AuNRs were obtained . The Au NVs were demonstrated with enhanced photothermal
behavior than that of individual AuNRs, owing to the plasmonic coupling effect of AuNRs inside the NVs.
In addition, the Au NVs can incorporate plasmid. Upon mild laser irradiation, the obtained Au NVs
underwent disassociation, initiating the release of plasmid followed by the spatiotemporal gene expression
at tumor sites. Intriguingly, with the later delivery of Ada-modified polysaccharide HA into cancer cells, the
reactivation of host-guest interaction promoted the aggregation of AuNRs, offering the possibility of gene-
photothermal synergistic therapy.

Three-in-one cancer therapy, via the combination of photothermal therapy, chemodynamic therapy and
chemotherapy, was constructed by Kong et al. utilizing host-guest interaction [Figure 7B] . In this case, a
[73]
reduced polyanionic cluster (rP W ) was employed as the core structure for the encapsulation of DOX,
18
2