To examine the photochemical properties of C2 a solution was prepared and irradiated with 375 nm light (1240 mW, incident intensity = 2.93 ± 0.08 * 10 15 determined by ferrioxalate actinometry (details in SI)). During a period of 60 minutes, aliquots were collected and analysed using UV/Vis spectroscopy (Figure ). We observed a linear decrease of absorbance (383 nm), indicating photodegradation of C2 (Figure , blue data), while the absorbance data collected for the non-irradiated control sample remained stable over time (Figure , black data). Photodegradation was confirmed by ESI-MS analysis were we found m/z = 319.12 ([M+H + ]) (Figure ), corresponding with the mass of the ketone photoproduct generated in the photodegradation process of C2 (Figure ). The photodegradation rate of C2 was calculated (C2 extinction coefficient = e383 27210 M -1 cm -1 (Figure )) according the collected UV/Vis (Figure and 3C) data and equals 6.8 * 10 -10 mol s -1 . Alternatively, the photodegradation process of C2 was monitored by 1 H-NMR analyses. Here we observed a linear decrease of the resonance at 4.03 ppm (in DMSO-d6) belonging to the a-carbon in C2 (indicated with asterisk, Figure and), indicating the photocleavage of the thioether. Additionally, the photodegradation rate was determined according the collected 1 H-NMR data (Figure ) and equals 6.5 * 10 -10 mol s -1 , which is in line with the degradation rate determined according the UV/Vis data. The quantum yield (f) of photodegradation for crosslinker C2 equals f = 0.14 calculated using UV/Vis data or f = 0.13 calculated using 1 H-NMR data, which is in line with reported values of comparable thioether phenacyl structures, and is higher than typical o-nitrobenzyl or o-nitroveratryl cages. Next, we prepared hydrogel patches (4 x 4 cm, thickness ~ 2 mm) loaded with BSA as a model protein (Figure ). First, a BSA stock solution (60 µl, 0.63 mg/ml, phosphate buffer (PB) (100 mM, pH 7.4)) was prepared and mixed with a dextran-alkyne solution (10 wt% in DMSO), which subsequently was mixed with a crosslinker C2 solution (400 µl, 4.61 µM, DMSO) containing Cu-click reactants (CuI 3.2 µM, DIPEA 8.6 µM,) and transferred to a quartz cuvette (4 x 4 x 4 cm) to gel overnight. After washing the hydrogel patches (details in SI), one hydrogel was irradiated with 375 nm light in order to degrade the hydrogel matrix and release the loaded BSA (66.5 kDa). Another hydrogel was kept in the dark as a control. During irradiation, aliquots were collected and subsequently analysed for their protein content by SDS-page gel analyses (sample mixture fluorescently labelled with NHS-Cy5, details in SI) (Figure , right lanes). Here, we observed an increasing trend in fluorescence intensity as irradiation time increases, indicating the release of BSA protein, while barely any fluorescent signal is observed in the non-irradiated control hydrogel after 24 hours (Figure , left lanes). The fluorescent protein band is located high (approximately at 500 kDa range) in the SDS-page gel, which is likely the result of resolubilized dextran polymer (500 kDa) during light irradiation, resulting in clogging of the SDS-page gel which prevents BSA to migrate freely through the SDS-page gel material. Since NHS-fluorescent labelling is specific towards protein amines, we are confident that we are observing the light triggered release of BSA protein from the dextran hydrogel matrix. This is supported by accompanying UV/Vis (NanoDrop) data we collected, which shows a linear increase of protein release reaching a 45% release efficiency after 24 hours of 375 nm light irradiation (Figure ). Encouraged by these results we decided to load human IgG in our hydrogel patches. Human IgG is an interesting model protein as antibodies and antibody drug conjugates (ADC) are potent anticancer agents. The molecular weight of human IgG is approximately 150 kDa which is 2.3 times heavier than BSA (66.5 kDa). Larger molecules typically diffuse slower from a hydrogel matrix. This allowed us to reduce the crosslinker C2 loading (25% lower initial C2 concentration) in our hydrogels while still hampering protein diffusion from the hydrogel matrix. To test antibody release, we prepared hydrogel patches as described before, and loaded human IgG (0.5 mg/ml). After gelation was complete, 375 nm light irradiation was started and the IgG release was quantified according a Bradford assay. We found a linear increase in IgG concentration with increasing irradiation time, reaching a release efficiency of 96% after 9 hours of 375 nm light irradiation (Figure ). Encouraged by our obtained results on light triggered protein release, we were curious if we could photodegrade our hydrogel using real CL, which would result in protein release. To test this, we prepared protein containing hydrogel patches of which one was placed in a 60 Co-source and one was kept aside as a control. The g-radiation emitted by a 60 Co source (0.6 kGy/h) generates low intensity light due to the Cerenkov effect, which could potentially trigger the photocleavage of crosslinker C2, resulting in the triggered release of the loaded proteins. However, we did not detect a significant amount of protein in the hydrogel's supernatant aqueous solution compared to the control hydrogel, indicating that the triggered release had failed. When visually inspecting the g-irradiated hydrogels we observed a remarkable contraction effect where the hydrogels consistently showed a macroscopic contraction of the hydrogel volume. Inspired by these results we started to investigate this contraction effect and found that the residual, unreacted alkyne moieties after initial Cu-click mediated crosslinking, form new alkyne-alkyne crosslinks. These secondary g-irradiation induced crosslinks result in an increased hydrogel stiffness and a significantly reduced hydrogel volume. Moreover, the diffusivity of the hydrogel loaded proteins is thus further restrained due to the increased crosslink density, which explains why no protein release was observed. All together, we were not able to perform proper CL triggered release experiments, due to the inference caused by the residual alkyne groups. For future hydrogel design we will have to carefully design the polymer backbone structure and avoid residual reactive groups that potentially could interfere with g-radiation. At present, CL-triggered release using phenacyl crosslinkers remains inconclusive.