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For centuries, a competitive evolutionary race between prokaryotes and related phages or other mobile genetic elements has led to the diversification of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated sequence (Cas) genome-editing systems. Among the different CRISPR/Cas systems, the CRISPR/Cas9 system has been widely studied for its precise DNA manipulation; however, due to certain limitations of direct DNA targeting, off-target effects and delivery challenges, researchers are looking to perform transient knockdown of gene expression by targeting RNA. In this context, the more recently discovered type VI CRISPR/Cas13 system, a programmable single-subunit RNA-guided endonuclease system that has the capacity to target and edit any RNA sequence of interest, has emerged as a powerful platform to modulate gene expression outcomes. All the Cas13 effectors known so far possess two distinct ribonuclease activities. Pre-CRISPR RNA processing is performed by one RNase activity, whereas the two higher eukaryotes and prokaryotes nucleotide-binding domains provide the other RNase activity required for target RNA degradation. Recent innovative applications of the type VI CRISPR/ Cas13 system in nucleic acid detection, viral interference, transcriptome engineering and RNA imaging hold great promise for disease management. This genome editing system can also be employed by the Specific High Sensitivity Enzymatic Reporter Unlocking platform to identify any tumor DNA. The discovery of this system has added a new dimension to targeting, tracking and editing circulating microRNA/RNA/DNA/cancer proteins for the management of cancer. However, there is still a lack of thorough understanding of the mechanisms underlying some of their functions. The present review summarizes the recent updates on the type VI CRISPR/Cas system in terms of its structural and mechanistic properties and some novel applications of this genome-editing tool in cancer management. However, some issues, such as collateral degradation of bystander RNA, impose major limitations on its in vivo application. Furthermore, additional challenges and future prospects for this genome editing system are described in the present review.

Cancer drug delivery remains a formidable challenge due to systemic toxicity and inadequate extravascular transport of nanotherapeutics to cells distal from blood vessels. It is hypothesized that, in absence of an external driving force, the Salmonella enterica serovar Typhimurium could be exploited for autonomous targeted delivery of nanotherapeutics to currently unreachable sites. To test the hypothesis, a nanoscale bacteria‐enabled autonomous drug delivery system (NanoBEADS) is developed in which the functional capabilities of the tumor‐targeting S. Typhimurium VNP20009 are interfaced with poly(lactic‐co‐glycolic acid) nanoparticles. The impact of nanoparticle conjugation is evaluated on NanoBEADS' invasion of cancer cells and intratumoral transport in 3D tumor spheroids in vitro, and biodistribution in a mammary tumor model in vivo. It is found that intercellular (between cells) self‐replication and translocation are the dominant mechanisms of bacteria intratumoral penetration and that nanoparticle conjugation does not impede bacteria's intratumoral transport performance. Through the development of new transport metrics, it is demonstrated that NanoBEADS enhance nanoparticle retention and distribution in solid tumors by up to a remarkable 100‐fold without requiring any externally applied driving force or control input. Such autonomous biohybrid systems could unlock a powerful new paradigm in cancer treatment by improving the therapeutic index of chemotherapeutic drugs and minimizing systemic side effects. Nanoscale bacteria‐enabled autonomous drug delivery system (NanoBEADS) agents are constructed by conjugating poly(lactic‐co‐glycolic acid) nanoparticles with tumor‐targeting Salmonella Typhimurium. NanoBEADS enhance retention and distribution of nanoparticles in solid tumors by up to a remarkable ≈100‐fold, through intercellular (between cells) self‐replication and translocation. This transport enhancement is achieved autonomously, without the need for any externally‐applied driving force or control input.

Multimodal therapy requires effective drug carriers that can deliver multiple drugs to specific locations in a controlled manner. Here, the study presents a novel nanoplatform constructed using zeolitic imidazolate framework‐8 ( Z IF‐8), a nanoscale metal‐organic framework nucleated under the mediation of silk fibroin ( S F). The nanoplatform is modified with the newly discovered MCF‐7 breast tumor‐targeting peptide, AREYGTRFSLIGGYR ( AR peptide). Indocyanine green ( I CG) and doxorubicin ( D OX) are loaded onto the nanoplatform with high drug encapsulation efficiency (>95%). ICG enables the resultant nanoparticles (NPs), called AR‐ZS/ID‐P, to release reactive oxygen species for photodynamic therapy ( P DT) and heat for photothermal therapy ( P TT) under near‐infrared (NIR) irradiation, promoting NIR fluorescence and thermal imaging to guide DOX‐induced chemotherapy. Additionally, the controlled release of both ICG and DOX at acidic tumor conditions due to the dissolution of ZIF‐8 provides a drug‐targeting mechanism in addition to the AR peptide. When intravenously injected, AR‐ZS/ID‐P NPs specifically target breast tumors and exhibit higher anticancer efficacy than other groups through ICG‐enabled PDT and PTT and DOX‐derived chemotherapy, without inducing side effects. The results demonstrate that AR‐ZS/ID‐P NPs are a promising multimodal theranostic nanoplatform with maximal therapeutic efficacy and minimal side effects for targeted and controllable drug delivery.

Human homeobox protein (Nanog) is highly expressed in most cancer cells and has gradually emerged as an excellent target in cancer therapy, owing to its regulation of cancer cell proliferation, metastasis and apoptosis. In this study, we prepared tumor-targeting functionalized selenium nanoparticles (RGDfC-SeNPs) to load chemotherapeutic doxorubicin (DOX) and Nanog siRNA. Herein, RGDfC peptide was used as a tumor-targeting moiety which could specifically bind to α β integrins overexpressed on various cancer cells. The sizes of RGDfC-SeNPs@DOX nanoparticles (~12 nm) were confirmed by both dynamic light scattering and transmission electron microscopy. The chemical structure of RGDfC-SeNPs@DOX was characterized via Fourier-transform infrared spectroscopy. The RGDfC-SeNPs@DOX was compacted with siRNA (anti-Nanog) by electrostatic interaction to fabricate the RGDfC-SeNPs@DOX/siRNA complex. The RGDfC-SeNPs@DOX/siRNA complex nanoparticles could efficiently enter into HepG2 cells via clathrin-associated endocytosis, and showed high gene transfection efficiency that resulted in enhanced gene silencing. The in vivo biodistribution experiment indicated that RGDfC-SeNPs@DOX/siRNA nanoparticles were capable of specifically accumulating in the tumor site. Furthermore, treatment with RGDfC-SeNPs@DOX/siRNA resulted in a more significant anticancer activity than the free DOX, RGDfC-SeNPs@DOX or RGDfC-SeNPs/siRNA in vitro and in vivo. In summary, this study shows a novel type of DOX and siRNA co-delivery system, thereby providing an alternative route for cancer treatment.

Pyroptosis, an inflammatory cell death, has attracted great attention for potentiating a strong immune response against tumor cells. However, developing powerful pyroptosis inducers and then activating specific pyroptosis still remains challenging. Herein, a PEG‐CuP‐COF@∆St nanosystem is rationally designed, consisting of PEG‐CuP‐COF nanozyme pyroptosis inducers and tumor‐targeting bacteria of the Salmonella Typhimurium strain VNP20009 (ΔSt), with an affinity for the tumor hypoxic microenvironment. The PEG‐CuP‐COF nanozymes possessed excellent sonodynamic performance and multienzyme‐mimicking activities to generate reactive oxygen species (ROS) and then induce potent pyroptosis. The superoxide dismutase‐ and peroxidase‐mimicking activities of PEG‐CuP‐COF catalytically produced hydrogen peroxide (H2O2) and hydroxyl radicals (•OH) which have important value in triggering acute inflammatory responses and pyroptosis. Moreover, PEG‐CuP‐COF showed outstanding glutathione peroxidase‐mimicking activities, impairing the antioxidant defense in tumor cells and enhancing sonodynamic efficiency by making them more vulnerable to ROS‐induced damage. During in vivo studies, PEG‐CuP‐COF@∆St nanosystem with its self‐driven property exhibited impressive tumor‐targeting capability and activated Caspase‐3/gasdermin E‐dependent pyroptosis to inhibit tumor growth. More importantly, it induced a powerful immune memory effect to prevent bone metastasis. In summary, this study introduces an innovative approach for combinatorial sono‐catalytic immunotherapy using bacteria‐mediated tumor‐targeting delivery of nanozymes as specific pyroptosis inducers. This study presents a novel PEG‐CuP‐COF@∆St nanosystem that consists of PEG‐CuP‐COF nanozyme pyroptosis inducers and tumor‐targeting bacteria of the Salmonella Typhimurium strain VNP20009 (ΔSt). The PEG‐CuP‐COF@∆St nanosystem can specifically induce pyroptosis in tumor cells. This strategy inhibits both primary and distant tumors and prevents bone metastasis, providing an innovative paradigm for combinatorial sono‐catalytic immunotherapy.

Oncolytic bacteria are the most promising tumor target vector. Questions also remain regarding finding a balance between the therapeutic efficacy and safety of oncolytic bacteria. The critical measure of how this balance is maintained is the improvement in tumor colonization. Attenuated Salmonella typhimurium (VNP20009) as the only Salmonella strain to be evaluated in a clinical trial is a potential tumor therapeutic bacterium. A delivery system with controlled release of VNP after being loaded into neutrophils, which significantly increases the tumor‐targeting of VNP and enhances its therapeutic efficacy in a melanoma lung metastasis model is constructed. To improve the synergistic therapeutic effect, a PD1 nanobody is applied to this system (NE(PD1nb)). NE(PD1nb) activate dendritic cells (DCs) differentiation and stimulate the M1‐like differentiation of macrophages, and induce CD4+ T‐cells maturity and cytotoxic CD8+ T‐cells activation through DCs tumor antigen presentation. Oncolytic bacteria delivery system based on neutrophil camouflage is developed to increase tumor colonization and safety. VNP‐PD1nb are loaded by neutrophils in vitro; NE(PD1nb) are transported along the blood vessels after intravenous injection and colonize in lung tumor foci. NE(PD1nb) induce antitumor immune response, thus, achieving consolidated therapy with bacteriotherapy, cell‐based immunotherapy, and immune checkpoint blockers immunotherapy.

Ultrasound‐generated antigens combined with TLR7/8 agonists as adjuvants have demonstrated significant anti‐tumor efficacy as an in‐situ vaccine. However, the use of TLR7/8 agonists can cause severe inflammatory responses. In this study, we present a novel tumor‐targeting nano‐adjuvant termed aPDL1‐PLG/R848 NPs, which are composed of aPDL1 antibody, Fc‐III‐4C peptide linker (Fc‐linker) and poly(L‐glutamic acid)‐grafted‐R848. Under ultrasound irradiation, antigen‐presenting cells activate immune mechanisms in vivo under dual stimulation of in situ antigens and immune adjuvants. The strategy inhibits primary tumor growth and induces a strong antigen‐specific immune memory effect to prevent tumor recurrence in vivo. This work offers a safe and potent platform for an in situ cancer vaccine based on ultrasound therapy. Ultrasound therapy induces in situ vaccination (ISV) by promoting tumor immunogenic death, and the tumor‐targeting nano‐adjuvant (aPDL1‐PLG/R848 NPs) enhances the ISV effect by tumor‐targeted delivery of R848, minimizing side effects. This synergy triggers a robust systemic antitumor immune response for in situ cancer vaccination.

In situ radiotherapy is the most successful cytotoxic therapy available for the treatment of solid tumors, while high‐dose radiotherapy per fraction is not yet widely and reliably used. To some extent, the major considerations of the disappointing results are on the risk of high‐dose irradiation‐induced damage to the surrounding normal tissues and the difficulty in distant metastasis control. To break these restraints, a gelatinase‐responsive amphiphilic methoxypolyethyleneglycol–PVGLIG–polycaprolactone (mPEG–PVGLIG–PCL) nanoparticles’ loading verteporfin (N@VP), a special photosensitizer that can also be excited by X‐rays to produce cytotoxic singlet oxygen and greatly enhance radiotherapy efficacy, is prepared in this study. Herein, it is shown that the formed N@VP combined with conventional‐dose radiation therapy (RT, 2 Gy (gray, a radiation dose unit)) can realize an antitumor effect no less than high‐dose RT (8 Gy) and minimize radiation dose necessary to achieve local tumor control. Moreover, this radiosensitive nanosystem can exert excellent systemic antitumor immunity and abscopal effect, providing a preferable “in situ vaccine” strategy based on conventional‐dose RT to achieve efficient systemic management of distant tumor metastasis. When combined with immunotherapy, this novel strategy for radiosensitization results in better immunotherapy sensitivity by stimulating significant immunogenic tumor cell death and synergistic antitumor immune responses. Here gelatinase‐responsive methoxypolyethyleneglycol–PVGLIG–polycaprolactone (mPEG–PVGLIG–PCL) nanoparticles’ loading verteporfin (N@VP) is developed, enhancing radiotherapy via X‐ray‐triggered singlet oxygen generation. Combined with 2 Gy (gray, a radiation dose unit) irradiation, N@VP achieves antitumor efficacy comparable to 8 Gy, and also promotes systemic antitumor immunity, abscopal effects, and synergizes with immunotherapy by inducing tumor cell pyroptosis, offering a more advantageous radiosensitization strategy for metastatic control based on conventional‐dose radiotherapy.

In this study, a glycyrrhetinic acid-functionalized mesoporous silica nanoparticle (MSN-GA) was prepared for active tumor targeting. MSN-GA exhibited satisfactory loading capacity for insoluble drugs, uniform size distribution, and specific tumor cell targeting. Glycyrrhetinic acid, a hepatocellular carcinoma-targeting group, was covalently decorated on the surface of MSN via an amido bond. The successful synthesis of MSN-GA was validated by the results of Fourier transform infrared spectroscopy, transmission electron microscopy (TEM), and zeta potential measurement. TEM images revealed the spherical morphology and uniform size distribution of the naked MSN and MSN-GA. Curcumin (CUR), an insoluble model drug, was loaded into MSN-GA (denoted as MSN-GA-CUR) with a high-loading capacity (8.78%±1.24%). The results of the in vitro cellular experiment demonstrated that MSN-GA-CUR significantly enhanced cytotoxicity and cellular uptake toward hepatocellular carcinoma (HepG2) cells via a specific GA receptor-mediated endocytosis mechanism. The results of this study provide a promising nanoplatform for the targeting of hepatocellular carcinoma.

The application of metal-based nanoparticles (mNPs) in cancer therapy and diagnostics (theranostics) has been a hot research topic since the early days of nanotechnology, becoming even more relevant in recent years. However, the clinical translation of this technology has been notably poor, with one of the main reasons being a lack of understanding of the disease and conceptual errors in the design of mNPs. Strikingly, throughout the reported studies to date on in vivo experiments, the concepts of “tumor targeting” and “tumor cell targeting” are often intertwined, particularly in the context of active targeting. These misconceptions may lead to design flaws, resulting in failed theranostic strategies. In the context of mNPs, tumor targeting can be described as the process by which mNPs reach the tumor mass (as a tissue), while tumor cell targeting refers to the specific interaction of mNPs with tumor cells once they have reached the tumor tissue. In this review, we conduct a critical analysis of key challenges that must be addressed for the successful targeting of either tumor tissue or cancer cells within the tumor tissue. Additionally, we explore essential features necessary for the smart design of theranostic mNPs, where ‘smart design’ refers to the process involving advanced consideration of the physicochemical features of the mNPs, targeting motifs, and physiological barriers that must be overcome for successful tumor targeting and/or tumor cell targeting.