The Development Of Biomaterials To Enhance Therapeutic Effect Triggered By Local Immune Regulation

The human immune system plays a key role in tissue homeostasis and the occurrence and development of diseases.Beyond defence against pathogens,it is implicated in autoimmune syndromes,allergies,cancer surveillance and pathogenesis,as well as in tissue repair and regenerative processes.Therefore,modulation of the immune system may enable the treatment of a wide variety of diseases.However,systemic immunomodulation often has potential life-threatening side effect in clinic.For example,systemic immunosuppression can control the symptoms of autoimmune syndromes at the cost of potential systemic complications.Cancer immunotherapies,such as checkpoint inhibitors,can boost antitumour immunity but also cause serious immune-related adverse events by disrupting homeostatic immune tolerance.Cellular immunotherapies can be engineered with higher specificity but suffer from high costs,long processing times and poor cell survival and target site homing following cell delivery.In the PhD dissertation,we have systematically studied a variety of local immune regulation and their mediated therapy strategies.Part I:Nanoscale Coordination Polymer based Nano-Vaccine for Tumor ImmunotherapyObjective:To investigate the fabrication of nanoscale coordination polymer(NCP)based Nano-Vaccine and combined effect with anti PD-1 antibody,a kind of checkpoint inhibitor.Methods:A unique OVA@Mn-DAP nanovaccine was fabricated by encapsulating the antigen protein OVA with NCPs formed by Mn2+ ions and DAP ligand,which is a Nod1 agonist,for tumor immunotherapy.Results:In this nano-vaccine,NCPs not only serve as the nano-carrier of antigen protein(e.g.OVA),but also offer the adjuvant function(by DAP)for enhancing tumor immunotherapy and the imaging function(by Mn2+)based on its own inherent composition.Such nanovaccine could facilitate the cellular uptake of antigen,stimulate maturation of DCs,enhance retention in LNs(lymph glands),and promote the antigen cross-presentation by activating the Nod1 pathway.Moreover,the T1 magnetic resonance(MR)contrasting ability of OVA@Mn-DAP could allow in vivo tracking of such nanovaccine by MR imaging,which uncovered its long-term retention in the lymph nodes after local injection.Importantly,OVA@Mn-DAP could not only be used as a prophylactic nano-vaccine to protect mice from melanoma challenge,but also as a therapeutic nano-vaccine to suppress the growth of established tumors and prolong animal survival time in combination with anti PD-1 antibody.Conclusion:We present an innovative strategy to construct NCP-based nano-vaccine for effective tumor immunotherapy by local injection.Part Ⅱ:Two-phase Releasing Immune-stimulating Composite Orchestrates Protection against Microbial InfectionsObjective:To investigate the fabrication of two-phase releasing immune-stimulating composite(MDP+P-M@ALG)and the fast,long-term,repeated,broad and effective protection against microbial infections.Methods:A two-phase releasing immune-stimulating composite(MDP+P-M@ALG)was developed by mixing ALG with MDP,a hydrosoluble Nod2 agonist,and the nanoparticle formulation of MPLA,a hydrophobic TLR 4 agonist,for microbial infection protection.Results:In this two-phase releasing immune-stimulating composite,MDP+P-M@ALG not only provide instantaneous sepsis protection by rapid release of MDP to activate innate immune cells(e.g.macrophage),but also offer long-term sepsis protection by sustained release of MPLA to continuously motivate the immune system.Such immune modulatory composite could initiate the immune system by up-regulating the production of various pro-inflammatory cytokines,promoting the M1 polarization of peritoneal macrophages and increasing the percentage of NK cells in the lesion after sepsis challenge.Furthermore,the two-phase releasing immune-stimulating composite could offer long-term protection against E.coli induced sepsis as well as CLP(cecal ligation and puncture)induced sepsis.Conclusion:We provide a two-phase releasing composite loaded with different immune modulatory agents for effective protection against sepsis under various triggering causes,promising for long-term and broad preventive effect of various infections.Part Ⅲ:ROS-Scavenging Hydrogel to Promote Healing of Bacteria Infected WoundsObjective:To investigate the fabrication of ROS-scavenging hydrogel and the effect for bacteria infected wound closure.Methods:A kind of ROS-scavenging hydrogel was developed and crosslinked by TPA,a ROS-responsive linker,and PVA.The ROS-scavenging hydrogel was loaded with the antibiotic mupirocin and the cytokine GM-CSF to promote healing of bacteria infected wounds.Results:Such ROS-scavenging hydrogel by itself could reduce the inflammation,decrease the secretion of various pro-inflammatory cytokines,increase the percent of M2 phenotype macrophages,and trigger the production of new blood vessels and collagen around the wound,so that to promote wound healing not only in healthy mice but also in diabetic mice.Moreover,the hydrogel loaded with the antibiotic mupirocin and the cytokine GM-CSF could release those therapeutic molecules in response to wound endogenous ROS,subsequently eliminate S.a.u.infection in the wound and further accelerate wound regeneration,in both normal mice and diabetic mice with S.a.u.infection.Conclusion:We provide a ROS-scavenging hydrogel loaded with different therapeutic contents for effective wound regeneration under various complex conditions,promising for treatment of difficult-to-heal wounds such as infected wounds.In summary,this doctoral dissertation presents a series of biomaterials-based local immune regulation and its mediated therapy strategies.Considering the good biocompatibility and biodegradability,our local drug delivery systems may hold substantial promises for future clinical translation.