Nanoparticle accumulation in liver may induce resistance to immune checkpoint blockade therapy

Despite immune checkpoint blockade(ICB)therapy has transformed cancer treatment,only 20.2%of these patients achieved a response.Understanding resistance mechanisms to ICB is important for the treatment of a wider population.In this work,we occasionally found that the silica nanoparticles(SiO_(2)NPs)accumulated in the liver can induce resistance to following ICB therapy to a subcutaneous tumor in mice.By analysis of T cells frequency,we uncovered that SiO_(2)NPs in the liver resulted in a siphoning of T cells from circulation to the liver by produced chemokines.In addition,liver immunosuppressive cells further inhibit the function and induce apoptosis of recruited T cells,leading to a systemic loss and reduced tumor infiltration of T cells,which contributes to poor responses to ICB therapy.However,such effect is not observed in poly(lactic-co-glycolic acid)(PLGA)NPs treated mice under the same conditions,likely due to their much lower immunogenicity in perturbing the liver immune microenvironment,indicating that cancer is not a local disease but an ecosystem that is linked to the distal environment.We further provide a new mechanism insight into ICB resistance induced by liver accumulation of nanoparticles.

Degradation-resistant implanted biomaterials establish an immunosuppressive microenvironment that induces T cell exhaustion by recruiting myeloid cells

Implanted biomaterials have transformed healthcare and the treatment of injury and disease,but their infuence on the local immune landscape remains unclear.Here we discovered that degradation-resistant titanium-based implants establish an immunosuppressive microenvironment by recruiting myeloid cells,including monocytes,macrophages,neutrophils,and myeloid-lineage dendritic cells.Unlike normal tissues,the tissues nearby implants exhibit an chronic inflamed and immunosuppressive status characterised by myeloid-rich,T cell-exhaustion gene signature by single-cell RNA sequencing.Vitamin C treatment provides an effective strategy to rescue the immunosuppressive microenvironment,which can be used as a regular supplement to reduce the risk of malignant cell survival around the implants.

The enhanced permeability and retention effect based nanomedicine at the site of injury

The enhanced permeability retention(EPR)effect based nanomedicine has been widely used for tumor targeting during the past decades.Here we unexpectedly observed the similar"EPR effect"at the site of iniury.We found that the temporary dilated and leaky blood vessels caused by the potent vasodilator histamine in response to injury allowed the injected nanoparticles to pass through the vasculature and reached the injured tissue.Our finding shows the potential underline mechanism of"EPR effect"at the injured site.By loading with antibiotics,we further demonstrated a new strategy for prevention of infection at the site of injury.

Implantable blood clot loaded with BMP-2 for regulation of osteoimmunology and enhancement of bone repair

The treatment of large-area bone defects still faces many difficulties and challenges.Here,we developed a blood clot delivery platform loaded with BMP-2 protein(BMP-2@BC)for enhanced bone regeneration.Blood clot gel platform as natural biomaterials can be engineered from autologous blood.Once implanted into the large bone defect site,it can be used for BMP-2 local delivery,as well as modulating osteoimmunology by recruiting a great number of macrophages and regulating their polarization at different stages.Moreover,due to the deep-red color of blood clot gel,mild localized hyperthermia under laser irradiation further accelerated bone repair and regeneration.We find that the immune niche within the bone defect microenvironment can be modulated in a controllable manner by the blood clots implantation and laser treatment.We further demonstrate that the newly formed bone covered almost 95%of the skull defect area by our strategy in both mice and rat disease models.Due to the great biocompatibility,photothermal potential,and osteoimmunomodulation capacity,such technology shows great promise to be used in further clinical translation.