Oxidative stress induced by excess reactive oxygen species (ROS) plays a significant role in the onset and progression of numerous skin disorders, necessitating effective antioxidant defenses to prevent and repair oxidative damage. However, existing systemic antioxidant therapies for skin diseases often fall short in efficiently delivering antioxidants to the diseased lesions. In this study, a novel non‐invasive transdermal delivery platform utilizing chitosan grafted with salcaprozate sodium (SCS) is designed for highly efficient delivery of biomolecular enzymes, such as catalase (CAT). After self‐assembling with catalase, the obtained SCS‐CAT nanocomplexes if topically applied in a cream demonstrate highly efficient skin penetration and accumulation. Owing to the ability of CAT to effectively scavenge ROS, topically applied SCS‐CAT nanocomplexes enable remarkable repair and protection effects against ultraviolet radiation B (UVB)‐induced skin photodamages by inhibiting cell apoptosis and inflammation. Moreover, such SCS‐CAT delivery platform holds promise for long‐term skin care applications due to its great biocompatibility. This research presents a simple yet transformative platform for the intradermal delivery of biological enzymes, presenting a promising avenue for treating various inflammatory skin disorders.

Therapeutic proteins are playing increasingly important roles in treating numerous types of diseases. However, oral administration of proteins, especially large ones (e.g., antibodies), remains a great challenge due to their difficulties in penetrating intestinal barriers. Herein, fluorocarbon-modified chitosan (FCS) is developed for efficient oral delivery of different therapeutic proteins, in particular large ones such as immune checkpoint blockade antibodies. In our design, therapeutic proteins are mixed with FCS to form nanoparticles, lyophilized with appropriate excipients, and then filled into enteric capsules for oral administration. It has been found that FCS could promote transmucosal delivery of its cargo protein via inducing transitory rearrangement of tight junction associated proteins between intestinal epithelial cells and subsequently release free proteins into blood circulation. It is shown that at a 5-fold dose oral delivery of anti-programmed cell death protein-1 (αPD1) or its combination with anti-cytotoxic T-lymphocyte antigen 4 (αCTLA4) using this method could achieve comparable antitumor therapeutic responses to that achieved by intravenous injection of corresponding free antibodies in various types of tumor models and, more excitingly, result in significantly reduced immune-related adverse events. Our work successfully demonstrates the enhanced oral delivery of antibody drugs to achieve systemic therapeutic responses and may revolutionize the future clinical usage of protein therapeutics.

Despite the approval of immune checkpoint blockade (ICB) for colorectal cancer treatment, its objective response rate remains to be improved, especially for non-immunogenic tumors. Moreover, systemically administrated ICB antibodies is usually associated with immune-related adverse effects (irAEs). Herein, we report novel oral administration of anti-programmed cell death protein L1 (anti-PD-L1) complexes for immunotherapy against colorectal tumors. Antibodies could form nanocomplexes with fluorocarbon modified chitosan (FCS) to acquire greatly improved transmucosal penetration ability, owing to the ability of FCS to reduce mucus binding and temporary open tight junctions between epithelial cells. As evidenced in orthotopic colorectal tumors on mice, orally administrated FCS/anti-PD-L1 nanocomplexes exhibited greatly improved intestinal permeability and significant intertumoral penetration, and if combined with oxaliplatin (OXA) chemotherapy to induce an immunogenic tumor phenotype, could finally inhibit the growth of tumors and prolong the animal survival. Notably, compared to systematic injection of anti-PD-L1, oral administration of FCS/anti-PD-L1 achieved comparable therapeutic efficacy with five-fold dosage, and exhibited reduced tendency of systemic irAEs as exhibited by the decreased percentage of Th17 cells in lymph nodes. Our work here provides a simple but effective strategy for immunotherapy by oral administration of ICB antibodies, achieving strong antitumor immune responses without the concern of systemic irAEs.

Immune checkpoint blockade (ICB) therapy has been considered as an effective way to boost immune cells to recognize and attack tumors. However, side effects known as immune-related adverse events (irAEs) should be carefully managed. Here, we engineer immunosuppressive nanoparticles by coating PD-L1 overexpressed mesenchymal stem cells (MSCs) plasma membrane on poly lactic-co-glycolic acid nanoparticles (MSC-PD-L1+ NPs) for managing and reducing irAEs induced by immune checkpoint inhibitors. The nanoparticles can enrich at liver site after intravenous administration. In the high dose of anti-PD-L1 mAb-induced irAEs clinically relevant mouse model, a low dose of MSC-PD-L1+ NPs (2 mg/kg) sufficiently rescues hepatitis by inactivating T cells and macrophages in the liver tissue. More intriguingly, due to the dose threshold for nanoparticles to the tumor site, we unexpectedly find that the injected NPs do not affect the efficiency of ICB therapy to inhibit solid tumor growth. Such a strategy shows potential for managing the various cancer immunotherapy associated irAEs in clinical applications.