Neutrophil Mediated Postoperative Photoimmunotherapy Against Melanoma Skin Cancer

Cancer has become one of the major diseases threatening human life and health.When the cell growth cycle is disturbed,it evolves into uncontrolled cancer cells,which migrate to noncancerous tissues and cause noncancerous tissues to become cancerous.Therefore,early diagnosis and treatment option of cancer cells is very important.If the cancer cells are not killed completely,it will spread and metastasize.Surgery is the main treatment option for most melanoma.However,high tumor recurrence rate after surgical resection becomes the main cause of death in cancer patients.Although chemotherapy has been combinde with surgical resection to kill the remained cancer cells,the effectiveness is limited.Development of drug delivery nanosystems to inhibit postoperative tumor recurrence becomes very necessary.Free drugs,such as small-molecule drugs,nucleic acids,and proteins in particular,with poor solubility,low stability,and poor membrane permeability,may cause rapid elimination,unsatisfactory biodistribution,and toxicity to normal tissues.Hence,boosted by great advances in nanotechnology,the nanoparticulate drug delivery systems,including liposomes and polymeric micelles,have gained great interest.Despite these notable achievements of nanoparticulate drug delivery systems,poor targetability is still the principal challenge.Take the nanoparticulate drug delivery systems as an example:Nearly all of the nanoparticles used were smaller than 200 nm in size and were able to passively target tumors through EPR effects.Although preferential accumulation of nanoparticles in tumors through EPR effects has been observed in mice with multiple tumor types,there was evidence that on average only 0.7%of injected nanoparticles were detected in tumor tissues.As the basic functional unit of organisms,cells are natural carriers for proteins and molecules,which has good biocompatibility,lower toxicity,and capability of crossing various biological barriers to release drug at tumor site by external cellular stimuli include inflammatory factors,micro-acid environment,light,etc.In the present study,IR780 molecule and TRP-2 peptide were encapsulated in the hydrophobic shell and hydrophilic interior of TAT peptide functionalized liposomes to form TLip IT NPs,which were further internalized into neutrophils(NEs)to achieve TLip IT/NEs.After intravenously injected into B16F10-bearing mice at 4 h postoperation,TLip IT/NEs could actively migrate toward the inflamed residual tumor and release _TLip IT in response to tumor microenvironment(TME).Under NIR laser irradiation,the _TLip IT exhibited both photothermal and photodynamic effects to induce immunogenic cell death for maturation of DCs,and simultaneously release TRP-2peptide as melanoma associated antigen to further strengthen the maturation of DCs,both of which prompt the activation of T cell and induce potent immune responses.TLip IT/NEs hold great potential for inhibition of postoperative tumor recurrence.