Conceptualization, C.-S.W. and Y.W.; Data curation, C.-S.W., S.-D.L., and C.-H.Y.; Formal analysis, C.-S.W., S.J., W.W., S.-F.C., S.-W.F., and C.-H.Y.; Funding acquisition, C.-S.W.; Investigation, C.-S.W. and Y.W.; Methodology, S.-D.L., S.J., W.W., S.-F.C., S.-W.F., and C.-H.Y.; Project administration, Y.W.; Resources, C.-S.W., S.-D.L., S.J., J.-H.L., and Y.W.; Software, S.J. and W.W.; Supervision, C.-S.W. and Y.W.; Validation, S.-D.L., S.J., W.W., S.-F.C., J.-H.L., and Y.W.; Writing—original draft preparation, Y.W.; Writing—review and editing, C.-S.W. and Y.W. All authors have read and agreed to the published version of the manuscript.

Figure 1. Formation of ADC based on complex coacervation. (A) Chemical structure of Och and IP6. (B) Effect of pH and molar ratio on the phase diagram of ADC complex formation as characterized by measuring the weight of formed ADC. (C) Fluorescence micrograph of ADC formation at different pH conditions. (D) ADC formation in the presence of salt and pH as characterized by UV spectrometer. Experiments were performed in triplicate. Scale bars = 20 µm.

Figure 1. Formation of ADC based on complex coacervation. (A) Chemical structure of Och and IP6. (B) Effect of pH and molar ratio on the phase diagram of ADC complex formation as characterized by measuring the weight of formed ADC. (C) Fluorescence micrograph of ADC formation at different pH conditions. (D) ADC formation in the presence of salt and pH as characterized by UV spectrometer. Experiments were performed in triplicate. Scale bars = 20 µm.

Figure 2. Properties of ADC. (A) ADC adhered to both glass and plastic surfaces. (B) Brightfield time-lapse photographs showed the liquid-like and flowable behavior of ADC underwater. Unit in minutes indicated by 0–10. (C) Time-lapse micrograph showed microdroplets fusing into a film-like structure of ADC in physiological conditions. Unit in minutes indicated by 0–5.5. (D) Stability of ADC at different pH conditions. Experiments were performed in triplicate.

Figure 2. Properties of ADC. (A) ADC adhered to both glass and plastic surfaces. (B) Brightfield time-lapse photographs showed the liquid-like and flowable behavior of ADC underwater. Unit in minutes indicated by 0–10. (C) Time-lapse micrograph showed microdroplets fusing into a film-like structure of ADC in physiological conditions. Unit in minutes indicated by 0–5.5. (D) Stability of ADC at different pH conditions. Experiments were performed in triplicate.

Figure 3. Drug encapsulation and release properties of ADC. (A) Different properties of compounds can be efficiently encapsulated into ADC. Abbreviations: ADC, adhesive drug carrier; AB, Alcian Blue; ORO, Oil Red O; PA, proanthocyanins; LG, Light Green SF. Scale bars = 50 µm. (B) PA release profiles at various pH conditions in the ADC system.

Figure 3. Drug encapsulation and release properties of ADC. (A) Different properties of compounds can be efficiently encapsulated into ADC. Abbreviations: ADC, adhesive drug carrier; AB, Alcian Blue; ORO, Oil Red O; PA, proanthocyanins; LG, Light Green SF. Scale bars = 50 µm. (B) PA release profiles at various pH conditions in the ADC system.

Figure 4. Treatment with ADC or ADC-PA does not affect the proliferation in nonactivated BMDM. (A) Immunofluorescence staining of the proliferation marker Ki67 in each group: Actin (red), Ki67 (green), and DNA (blue). The results from three independent experiments and representative images are shown. Scale bars = 50 μm. (B) Statistical analysis of Ki67-positive cells in each group. The results from six independent experiments are presented as the mean ± SD. * p < 0.05.

Figure 4. Treatment with ADC or ADC-PA does not affect the proliferation in nonactivated BMDM. (A) Immunofluorescence staining of the proliferation marker Ki67 in each group: Actin (red), Ki67 (green), and DNA (blue). The results from three independent experiments and representative images are shown. Scale bars = 50 μm. (B) Statistical analysis of Ki67-positive cells in each group. The results from six independent experiments are presented as the mean ± SD. * p < 0.05.

Figure 5. Treatment with ADC-PA alters LPS-mediated gene expression in BMDM. qPCR analysis of (A) pro-inflammatory cytokines and (B) anti-inflammatory cytokines in BMDMs treated with or without ADC or ADC-PA in the presence of LPS stimulation for 24 h. * indicates groups compared to PBS, # indicates groups compared to LPS, % indicates groups compared to ADC, & indicates groups compared to ADC+LPS, ^ indicated groups compared to ADC-PA, and § indicates groups compared to ADC-PA+LPS. The results from six independent experiments are presented as the mean ± SD. *, #, %, &, and § indicates p < 0.05.

Figure 5. Treatment with ADC-PA alters LPS-mediated gene expression in BMDM. qPCR analysis of (A) pro-inflammatory cytokines and (B) anti-inflammatory cytokines in BMDMs treated with or without ADC or ADC-PA in the presence of LPS stimulation for 24 h. * indicates groups compared to PBS, # indicates groups compared to LPS, % indicates groups compared to ADC, & indicates groups compared to ADC+LPS, ^ indicated groups compared to ADC-PA, and § indicates groups compared to ADC-PA+LPS. The results from six independent experiments are presented as the mean ± SD. *, #, %, &, and § indicates p < 0.05.

Figure 6. The long-term influence of ADC-PA on M2-associated gene expression of BMDM. qPCR analysis of (A) M1 and (B) M2-associated genes in BMDMs treated with ADC-PA at different time points (0 h, 6 h, and 48 h). The results from six independent experiments are presented as the mean ± SD. * p < 0.05, compared to 0 h.

Figure 6. The long-term influence of ADC-PA on M2-associated gene expression of BMDM. qPCR analysis of (A) M1 and (B) M2-associated genes in BMDMs treated with ADC-PA at different time points (0 h, 6 h, and 48 h). The results from six independent experiments are presented as the mean ± SD. * p < 0.05, compared to 0 h.

Figure 7. Induction of BMDM polarization by ADC-PA. (A) A heat map represents the relative expression levels of M1 and M2 markers in BMDM treated with different conditions: PBS, ADC, LPS, ACD+LPS, ADC-PA, and ADC-PA+LPS. The color scale represents the scaled abundance of each condition, with yellow indicating high abundance and red indicating low abundance. (B) Two-dimensional PCA (2D-PCA) score plots generated by analysis of each treatment condition, with circled regions illustrating the respective 95% confidence intervals. PC1 and PC2 describe 39.9% and 22.2% of the variance between the samples, respectively. Colored dots represent individual biological replicates. Experiments were conducted in triplicate.

Figure 7. Induction of BMDM polarization by ADC-PA. (A) A heat map represents the relative expression levels of M1 and M2 markers in BMDM treated with different conditions: PBS, ADC, LPS, ACD+LPS, ADC-PA, and ADC-PA+LPS. The color scale represents the scaled abundance of each condition, with yellow indicating high abundance and red indicating low abundance. (B) Two-dimensional PCA (2D-PCA) score plots generated by analysis of each treatment condition, with circled regions illustrating the respective 95% confidence intervals. PC1 and PC2 describe 39.9% and 22.2% of the variance between the samples, respectively. Colored dots represent individual biological replicates. Experiments were conducted in triplicate.

Figure 8. Ex vivo influence of ADC-PA on M2 macrophage polarization. (A) Schematic diagram showing the procedure to collect thioglycollate-elicited peritoneal macrophages from mice treated with different conditions. IF: immunofluorescence. (B) Immunofluorescence studies showed an increase of Arg-1-positive M2 macrophages and a decrease of iNOS-positive M1 macrophages in thioglycollate-elicited peritoneal macrophages from mice treated with ADC-PA. Scale bars = 50 μm. (C) Statistical graph showing relative expression ratio of Arg-1+/iNOS+ cells in different groups. Data are mean ± SEM of multiple fields in n = 5 per group. *, p < 0.05.

Figure 8. Ex vivo influence of ADC-PA on M2 macrophage polarization. (A) Schematic diagram showing the procedure to collect thioglycollate-elicited peritoneal macrophages from mice treated with different conditions. IF: immunofluorescence. (B) Immunofluorescence studies showed an increase of Arg-1-positive M2 macrophages and a decrease of iNOS-positive M1 macrophages in thioglycollate-elicited peritoneal macrophages from mice treated with ADC-PA. Scale bars = 50 μm. (C) Statistical graph showing relative expression ratio of Arg-1+/iNOS+ cells in different groups. Data are mean ± SEM of multiple fields in n = 5 per group. *, p < 0.05.

Figure 9. Healing effects of ADC-PA on full-thickness wounds in diabetic db/db mice. (A) Schematic diagram showing the procedure to generate a 7 mm full-thickness wound in db/db diabetic mice. (B) Representative images of wounds from each group over a 14-day period post-wounding. Nexcare liquid bandage solution was used as a positive control. Scale bar = 5 mm. (C) The graphical representation of the average wound closure in each group was measured using ImageJ software. (D) Masson’s Trichrome-stained skin tissue sections on days 7 and 14. Top panel scale bars = 1 mm. Middle panel scale bars = 200 μm. Lower panel scale bars = 100 μm. Orange dash lines indicate the wound site. Yellow dash lines distinguish the border between the epidermis and the dermis. Abbreviations: E, epidermis; D, dermis; G, granulation area. (E) Graphical representation of the expression of granulation thickness, collagen deposition, and epidermis thickness. The values are shown as mean ± SEM (n = 6 mice). * p < 0.05, ** p < 0.01, vs. the control group.

Figure 9. Healing effects of ADC-PA on full-thickness wounds in diabetic db/db mice. (A) Schematic diagram showing the procedure to generate a 7 mm full-thickness wound in db/db diabetic mice. (B) Representative images of wounds from each group over a 14-day period post-wounding. Nexcare liquid bandage solution was used as a positive control. Scale bar = 5 mm. (C) The graphical representation of the average wound closure in each group was measured using ImageJ software. (D) Masson’s Trichrome-stained skin tissue sections on days 7 and 14. Top panel scale bars = 1 mm. Middle panel scale bars = 200 μm. Lower panel scale bars = 100 μm. Orange dash lines indicate the wound site. Yellow dash lines distinguish the border between the epidermis and the dermis. Abbreviations: E, epidermis; D, dermis; G, granulation area. (E) Graphical representation of the expression of granulation thickness, collagen deposition, and epidermis thickness. The values are shown as mean ± SEM (n = 6 mice). * p < 0.05, ** p < 0.01, vs. the control group.

Figure 10. Significant macrophage polarization from M1 to M2 subtype occurs in the ADC-PA treated group. (A) Representative fluorescence micrographs showed wounded skin immunostained with M1 marker iNOS (green) and M2 marker CD206 (red) at days 7 and 14. Scale bars = 200 μm. (B) The number of M1 macrophages (iNOS+/CD206−) and M2 macrophages (Cd206+ iNOS−) per field in skin were statistically analyzed using ImageJ. The values are shown as mean ± SEM (n = 6 mice). * p < 0.05, vs. the control group. Abbreviations: iNOS, inducible nitric oxide synthase.

Figure 10. Significant macrophage polarization from M1 to M2 subtype occurs in the ADC-PA treated group. (A) Representative fluorescence micrographs showed wounded skin immunostained with M1 marker iNOS (green) and M2 marker CD206 (red) at days 7 and 14. Scale bars = 200 μm. (B) The number of M1 macrophages (iNOS+/CD206−) and M2 macrophages (Cd206+ iNOS−) per field in skin were statistically analyzed using ImageJ. The values are shown as mean ± SEM (n = 6 mice). * p < 0.05, vs. the control group. Abbreviations: iNOS, inducible nitric oxide synthase.

Figure 11. Schematic illustration of ADC-PA-guided macrophage reprogramming. ADC-PA treatment on wounds induces a conversion of M1 to M2 macrophages at an equilibrium phase and accelerates diabetic wound healing. Abbreviations: E, epidermis; D, dermis; H, hypodermis.

Figure 11. Schematic illustration of ADC-PA-guided macrophage reprogramming. ADC-PA treatment on wounds induces a conversion of M1 to M2 macrophages at an equilibrium phase and accelerates diabetic wound healing. Abbreviations: E, epidermis; D, dermis; H, hypodermis.