| Tumor immunotherapy has long-lasting and extensive anti-tumor effects,which can suppress the progress and metastasis of tumor by regulating the human immune system.At present,it is regarded most likely method to eliminate tumors as the fourth treatment method after surgical,radiotherapy,chemical drug treatment and targeted drug treatment.The immune checkpoints method is one of the most promising methods in tumor immunotherapy.It blocks immune suppressive signaling pathways through immune checkpoint inhibitors and then restores the immune system.The overexpression PD-L1 is an important immunoinhibitory molecule that suppresses the activation of T cells,leading to the survival and expansion of tumor cells.Blocking the interactions between PD-1/PD-L1 might enable T cells to attack the tumor,resulting in tumor rejection or apoptosis.PD-L1 antibody inhibitors have achieved significant results in clinic,which can permanently eliminate tumors in the part of patients,but there are also many problems.For example: the poor penetration of monoclonal antibody drugs in solid tumors has seriously reduced its clinical efficacy;the complicated preparation process makes it expensive;in order to achieve a strong immune effect,blindly increasing the dose makes the extremely prominent immune side effects.Peptide drugs have broad prospects in the future.They are inexpensive,easy preparation and highly biocompatible.Compared with monoclonal antibodies,their natural high penetration ability allows them to fully penetrate deep into solid tumor tissues.Therefore,in this work,peptide materials are selected as PD-L1 inhibitors for experimental research.Through ingenious design,we develope a click reaction-assisted immune checkpoint blockade(CRICB)strategy to in situ construct PD-L1-targeted peptide assembly.Firstly,the free DBCO-modified targeting peptide(TP)efficiently recognized and bound PD-L1 in deep tumor cells.Upon reagent-free click reaction with subsequently introduced azid-tethered self-assembling peptide(AP)after 20 mintunes,the resultant product spontaneously self-aggregation in situ and stably blocked PD-L1.The results show that the CRICB strategy can effectively achieve in situ blocking therapy in vivo.The constructed nanofibers can stably exist and extend the PD-L1 occupancy time.On the 4T1 tumor-bearing mouse model,the CRICB strategy has a very high penetration ability,and its penetration depth is 6 times that of monoclonal antibodies.The retention effect can still reach 50% after 5 days.In the treatment experiment,the CRICB strategy has a high-performance tumor inhibition,which is twice that of the antibody group.Moreover,the strategy has excellent biocompatibility and no toxic or side effects.In summary,we developed a click reaction-assisted peptide immune checkpoint blockade(CRICB)strategy to in situ construct peptide-based nanofibers which could specifically block PD-L1,enabling optimal penetration and accumulation,ultimately achieve tumor inhibition in vitro and in vivo. |
