Near-infrared (NIR) light-responsive, injectable hydrogels are among the most promising drug delivery systems for localized anticancer therapy owing to its minimally invasive administration and remotecontrolled manner. However, most currently reported NIR-responsive hydrogels were usually generated through physical mixing of thermosensitive polymers and photothermal conversion agents. In this study, a novel type of dynamic-covalent hydrogel (GelPV-DOX-DBNP) with NIR light-triggered drug release behavior was rationally designed for chemo-photothermal combination treatment of tumors. Concretely, this NIR-responsive hydrogel was formed by specific benzoxaborole-carbohydrate interactions between benzoxaborole (BOB)-modified hyaluronic acid (BOB-HA) and fructosebased glycopolymer (PolyFru), where photosensitizer perylene diimide zwitterionic polymer (PDS), reductant ascorbic acid (Vc), anticancer drug doxorubicin (DOX) as well as photothermal nanoparticles (DB-NPs) were encapsulated, simultaneously. Upon 660 nm light irradiation, both PDS and Vc within the designed hydrogel can convert oxygen into hydrogen peroxide, which could make hydrogel be degraded through the breakage of dynamic covalent bonds based on benzoxaborole-carbohydrate interactions, leading to NIR light-activatable release of DOX and DB-NPs from GelPV-DOX-DBNP. Furthermore, the released DB-NPs can convert 915 nm light irradiation into heat, enabling the application of GelPV-DOX-DBNP as a NIR-responsive drug delivery platform for both chemotherapy and photothermal therapy (PTT). In vivo results prove that GelPV-DOX-DBNP exhibited a markedly enhanced chemo-photothermal synergistic therapy for 4T1 tumor model mice, compared to chemotherapy alone or PTT. This work presents a new strategy to construct NIR lightresponsive hydrogel as one alternative drug delivery system for anticancer applications.

Optical imaging-guided chemo-photothermal combination therapy of cancers has attracted considerable attention, because of its capacity for personalized, precision treatment and its synergistic chemo-photothermal therapeutic effect. However, it still encounters many barriers, including an unsatisfactory diagnostic accuracy, poor physiological stability, low drug loading, and uncontrolled drug release. Here, we developed a NIR-II dye-based multifunctional telechelic glycopolymer (TTQ-TC-PFru) as a drug carrier and constructed stimuli-responsive PFru-BTZ-PBOB nanoparticles (NPs) to achieve the nearinfrared IIa (NIR-IIa, 1300-1400 nm) fluorescence imaging (FI)-guided chemo-photothermal combination therapy of cancers. This multifunctional glycopolymer not only serves as the contrast agent for NIR-IIa FI but also functions as the photothermal agent for photothermal therapy (PTT). Meanwhile, the fructose polymer on TTQ-TC-PFru forms a stable boronic acid-catechol conjugate with the dipeptidyl boronic acid proteasome inhibitor bortezomib (BTZ) to achieve high drug loading (31%), satisfactory physiological stability, and controlled drug release in the acidic tumor microenvironment. In addition, one BOB-containing copolymer POEGMA-co-PBOB was introduced to further improve the stability of the system. In living tumor-bearing mice, the successfully constructed stimuli-responsive NPs PFru-BTZ-PBOB induced significant tumor regression through NIR-IIa FI-guided chemo-photothermal combination therapy. Our study thus describes the great potential of NIR-IIa FI-guided chemo-photothermal combination therapy of cancers.

A glycopolymer modified water-soluble conjugated polymer brush was developed for Hep G2 tumor targeted photodynamic therapy.

A biocompatible zwitterionic polymer (PDS-PDI) was designed for PAI guided synergistic PDT and PTT with single NIR light irradiation.