RESUMO
Combination therapy that could better balance immune activation and suppressive signals holds great potential in cancer immunotherapy. Herein, we serendipitously found that the pH-responsive nanovesicles (pRNVs) self-assembled from block copolymer polyethylene glycol-b-cationic polypeptide can not only serve as a nanocarrier but also cause immunogenic cell death (ICD) through preapoptotic exposure of calreticulin. After coencapsulation of a photosensitizer, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) and an indoleamine 2,3-dioxygenase inhibitor, indoximod (IND), pRNVs/HPPH/IND at a single low dose elicited significant antitumor efficacy and abscopal effect following laser irradiation in a B16F10 melanoma tumor model. Treatment efficacy attributes to three key factors: (i) singlet oxygen generation by HPPH-mediated photodynamic therapy (PDT); (ii) increased dendritic cell (DC) recruitment and immune response provocation after ICD induced by pRNVs and PDT; and (iii) tumor microenvironment modulation by IND via enhancing P-S6K phosphorylation for CD8+ T cell development. This study exploited the nanocarrier to induce ICD for the host's immunity activation. The "all-in-one" smart nanovesicles allow the design of multifunctional materials to strengthen cancer immunotherapy efficacy.
Assuntos
Antineoplásicos/farmacologia , Morte Celular Imunogênica/efeitos dos fármacos , Imunoterapia , Melanoma/terapia , Nanopartículas/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Concentração de Íons de Hidrogênio , Morte Celular Imunogênica/imunologia , Melanoma/imunologia , Melanoma/patologia , Camundongos , Estrutura Molecular , Tamanho da Partícula , Peptídeos/química , Peptídeos/farmacologia , Fármacos Fotossensibilizantes/química , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Propriedades de Superfície , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) genome-editing system has shown great potential in biomedical applications. Although physical approaches, viruses, and some nonviral vectors have been employed for CRISPR/Cas9 delivery and induce some promising genome-editing efficacy, precise genome editing remains challenging and has not been reported yet. Herein, second near-infrared window (NIR-II) imaging-guided NIR-light-triggered remote control of the CRISPR/Cas9 genome-editing strategy is reported based on a rationally designed semiconducting polymer brush (SPPF). SPPF can not only be a vector to deliver CRISPR/Cas9 cassettes but also controls the endolysosomal escape and payloads release through photothermal conversion under laser irradiation. Upon laser exposure, the nanocomplex of SPPF and CRISPR/Cas9 cassettes induces effective site-specific precise genome editing both in vitro and in vivo with minimal toxicity. Besides, NIR-II imaging based on SPPF can also be applied to monitor the in vivo distribution of the genome-editing system and guide laser irradiation in real time. Thus, this study offers a typical paradigm for NIR-II imaging-guided NIR-light-triggered remote control of the CRISPR/Cas9 system for precise genome editing. This strategy may open an avenue for CRISPR/Cas9 genome-editing-based precise gene therapy in the near future.