Poor water solubility and low bioavailability of active pharmaceutical ingredients (APIs) are major causes of friction in the pharmaceutical industry and represent a formidable hurdle for pharmaceutical drug development. Drug delivery remains the major challenge for the application of new small‐molecule drugs as well as biopharmaceuticals. The three challenges for synthetic delivery systems are: (i) controlling drug distribution and clearance in the blood; (ii) solubilizing poorly water‐soluble agents, and (iii) selectively targeting specific tissues. Although several polymer‐based systems have addressed the first two demands and have been translated into clinical practice, no targeted synthetic drug delivery system has reached the market. This Review is designed to provide a background on the challenges and requirements for the design and translation of new polymer‐based delivery systems. This report will focus on chemical approaches to drug delivery for systemic applications.

Infectious wounds occur when harmful microorganisms such as bacteria or viruses invade a wound site. Its problems associated include delayed healing, increased pain, swelling, and the potential for systemic infections. Therefore, developing new wound dressing materials with antibacterial effects is crucial for improving the healing process. Here a redox‐degradable hydrogel loaded with an antibacterial peptide (vancomycin) in a straightforward gram‐scale synthesis, is developed. The hydrogel structure consists of a disulfide bond‐containing hyperbranched polyglycerol (SS‐hPG) that is cross‐linked by 4‐arm polyethylene glycol‐thiol (4‐arm PEG‐SH). The polymerization mechanism and full characterization of SS‐hPG are described as this synthesis is reported for the first time. Rheology is used to ascertain the hydrogel's mechanical characteristics, such as stiffness, and self‐healing, determining these properties for different ratios and concentrations of both gel components. The incorporation of disulfide bonds in the hydrogel is proved by conducting degradation experiments in reductive environments. Fluorescein isothiocyanate‐albumin (FITC‐BSA) and vancomycin both are loaded into the gel, and the guest release kinetics is assessed for both slow and on‐demand releases. Finally, the in vitro and in vivo experiments prove that the vancomycin‐loaded hydrogel acts as an antibacterial barrier for wound dressing and accelerates the healing of infectious wounds in a mouse model.

In Nature, most known objects can perform their functions only when in supramolecular self‐assembled from, e.g. protein complexes and cell membranes. Here, a dendritic polymer is presented that inhibits severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) with an irreversible (virucidal) mechanism only when self‐assembled into a Two‐dimmensional supramolecular polymer (2D‐SupraPol). Monomeric analogs of the dendritic polymer can only inhibit SARS‐CoV‐2 reversibly, thus allowing for the virus to regain infectivity after dilution. Upon assembly, 2D‐SupraPol shows a remarkable half‐inhibitory concentration (IC₅₀ 30 nM) in vitro and in vivo in a Syrian Hamster model has a good efficacy. Using cryo‐TEM, it is shown that the 2D‐SupraPol has a controllable lateral size that can be tuned by adjusting the pH and use small angle X‐ray and neutron scattering to unveil the architecture of the supramolecular assembly. This functional 2D‐SupraPol, and its supramolecular architecture are proposed, as a prophylaxis nasal spray to inhibit the virus interaction with the respiratory tract.

Inflammatory skin diseases, such as psoriasis, atopic dermatitis, and alopecia areata, occur when the regulatory tolerance of the innate immune system is disrupted, resulting in the activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) inflammatory signaling pathway by interleukin 6 (IL-6) and other key inflammatory cytokines. JAK inhibitors, such as tofacitinib, bind to these enzymes which are coupled to receptors on cell surfaces and block the transcription of inflammatory cytokine-induced genes. The first topical applications are being marketed, yet insufficient effects regarding indications, such as alopecia areata, suggest that improved delivery technologies could help increase the efficacy. In this study, we used sulfated dendritic polyglycerol with caprolactone segments integrated in its backbone (dPGS-PCL), with a molecular weight of 54 kDa, as a degradable carrier to load and solubilize the hydrophobic drug tofacitinib (TFB). TFB loaded in dPGS-PCL (dPGS-PCL@TFB), at a 11 w/w% loading capacity in aqueous solution, showed in an ex-vivo human skin model better penetration than free TFB in a 30:70 (v/v) ethanol/water mixture. We also investigated the anti-inflammatory efficacy of dPGS-PCL@TFB (0.5 w/w%), dPGS-PCL, and free TFB in the water/ethanol mixture by measuring their effects on IL-6 and IL-8 release, and STAT3 and STAT5 activation in ex vivo skin models of simulated inflamed human skin. Our results suggest that dPGS-PCL@TFB reduces the activation of STAT3 and STAT5 by increasing the penetration of the tofacitinib. However, no statistically significant differences with respect to the inhibition of IL-6 and IL-8 were observed in this short incubation time.