Although immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy, a monotherapy approach is not sufficient. Here, we report an immune checkpoint inhibitor-modified nanoparticle for an in situ-assembled tumor vaccine that can activate immune systems in the tumor microenvironment and prevent the long-term recurrence of tumors. Adjuvant-loaded nanoparticles were prepared by entrapping imiquimod (IQ) in photoresponsive polydopamine nanoparticles (IQ/PNs). The surfaces of IQ/PNs were then modified with anti-PDL1 antibody (PDL1Ab-IQ/PNs) for in situ assembly with inactivated tumor cells and immune checkpoint blocking of PDL1 (programmed cell death 1 ligand 1). The presence of anti-PDL1 antibodies on IQ/PNs increased the binding of nanoparticles to CT26 cancer cells overexpressing PDL1. Subsequent near-infrared (NIR) irradiation induced a greater photothermal anticancer effect against cells treated with PDL1Ab-IQ/PNs than cells treated with plain PNs or unmodified IQ/PNs. To mimic the tumor microenvironment, we cocultured bone marrow-derived dendritic cells with CT26 cells treated with various nanoparticle formulations and NIR irradiated. This coculture study revealed that NIR-inactivated, PDL1Ab-IQ/PN-bound CT26 cells induced maturation of dendritic cells to the greatest extent. Following a single intravenous administration of different nanoparticle formulations in CT26 tumor-bearing mice, PDL1Ab-IQ/PNs showed greater tumor tissue accumulation than unmodified nanoparticles. Subsequent NIR irradiation of mice treated with PDL1Ab-IQ/PNs resulted in tumor ablation. In addition to primary tumor ablation, PDL1Ab-IQ/PNs completely prevented the growth of a secondarily challenged CT26 tumor at a distant site, producing 100% survival for up to 150 days. A long-term protection study revealed that treatment with PDL1Ab-IQ/PNs followed by NIR irradiation inhibited the growth of distant, secondarily challenged CT26 tumors 150 days after the first tumor inoculation. Moreover, increased infiltration of T cells was observed in tumor tissues treated with PDL1Ab-IQ/PNs and NIR-irradiated, and T cells isolated from splenocytes of mice in which tumor recurrence was prevented showed active killing of CT26 cells. These results suggest that PDL1Ab-IQ/PNs in conjunction with NIR irradiation induce a potent, in situ-assembled, all-in-one tumor vaccine with adjuvant-containing nanoparticle-bound, inactivated tumor cells. Such in situ nanoadjuvant-assembled tumor vaccines can be further developed for long-term prevention of tumor recurrence without the need for chemotherapy.

Gene-editing technology is an emerging therapeutic modality for manipulating the eukaryotic genome by using target-sequence-specific engineered nucleases. Because of the exceptional advantages that gene-editing technology offers in facilitating the accurate correction of sequences in a genome, gene editing-based therapy is being aggressively developed as a next-generation therapeutic approach to treat a wide range of diseases. However, strategies for precise engineering and delivery of gene-editing nucleases, including zinc finger nucleases, transcription activator-like effector nuclease, and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-associated nuclease Cas9), present major obstacles to the development of gene-editing therapies, as with other gene-targeting therapeutics. Currently, viral and non-viral vectors are being studied for the delivery of these nucleases into cells in the form of DNA, mRNA, or proteins. Clinical trials are already ongoing, and in vivo studies are actively investigating the applicability of CRISPR/Cas9 techniques. However, the concept of correcting the genome poses major concerns from a regulatory perspective, especially in terms of safety. This review addresses current research trends and delivery strategies for gene editing-based therapeutics in non-clinical and clinical settings and considers the associated regulatory issues.

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Gene therapy has been receiving widespread attention due to its unique advantage in regulating the expression of specific target genes. In the field of cancer gene therapy, modulation of gene expression has been shown to decrease oncogenic factors in cancer cells or increase immune responses against cancer. Due to the macromolecular size and highly negative physicochemical features of plasmid DNA, efficient delivery systems are an essential ingredient for successful gene therapy. To date, a variety of nanostructures and materials have been studied as nonviral gene delivery systems. In this review, we will cover nonviral delivery strategies for cancer gene therapy, with a focus on target cancer genes and delivery materials. Moreover, we will address current challenges and perspectives for nonviral delivery-based cancer gene therapeutics.