Tumour targetable and microenvironment-responsive nanoparticles simultaneously disrupt the PD-1/PD-L1 pathway and MAPK/ERK/JNK pathway for efficient treatment of colorectal cancer

The present study was aimed to develop a novel combination therapeutic strategy of gene therapy and immunotherapy for efficiently treatment of colorectal cancer (CRC). To achieve that goal, the polyethylene glycol-modified poly (2-(N,N-dimethylamino) ethyl methacrylate) (PEG-PDMAEMA)-based nanoparticles loaded with protein tyrosine phosphatase non-receptor type 6 (PTPN6) (NP-PTPN6) was developed first followed by conjugation with anti-PD-L1 monoclonal antibodies (aPD-L1) atezolizumab (aPD-L1NP-PTPN6). Importantly, the aPD-L1 was conjugated on the surface of NP-PTPN6 by the matrix metalloproteinases (MMPs)-cleavable linkage PLGLAG. Therefore, the aPD-L1 would be completely released once the aPD-L1NP-PTPN6 was entrapped into tumour tissues as demonstrated by the release assay. Tumour targeting assay demonstrated the aPD-L1NP-PTPN6 have high affinity to CRC cells and resulted in excellent tumour targeting drug delivery efficacy. Additionally, anti-tumour effect evaluation revealed that the aPD-L1NP-PTPN6 has greater ability to inhibit the growth, invasion and migration of CRC cells and finally led to longer survival time of tumour-bearing mice than other treatments. Further mechanisms studies demonstrated that treatment of CRC cells with aPD-L1NP-PTPN6 contributed to significant suppression of the MAPK/ERK signalling pathway. Besides, it was further demonstrated that treating CRC with aPD-L1NP-PTPN6 resulted in up-regulation of NK cells and T cells percentage within the tumour tissues.