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. 2023 Jul 27;3(6):584–599. doi: 10.1021/acsmaterialsau.3c00035

Combinational Gene Therapy toward Cancer with Nanoplatform: Strategies and Principles

Jinhui Lin †,‡, Xinlian Wang †,‡, Dongqi Ni †,‡, Yandong Chen †, Chunying Chen †,‡, Ying Liu †,*
PMCID: PMC10636764  PMID: 38089659

Abstract

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Cancer remains a significant threat to human health. While numerous therapies have been developed to combat the disease, traditional treatments such as chemotherapy and radiotherapy are suboptimal and associated with significant side effects. Gene therapy is an emerging therapeutic approach that offers improved targeting and reduced side effects compared with traditional treatments. Using siRNA and other nucleic acid-based drugs in cancer treatment has generated significant interest among researchers. Nanocarriers, such as liposomes, can effectively deliver these agents to tumor sites. However, gene therapy alone is often insufficient to eradicate tumors, and there is a risk of recurrence. Therefore, combining gene therapy with other therapies using nanocarriers, such as phototherapy and magnetic hyperthermia therapy, can lead to synergistic therapeutic effects through different mechanisms. In this review, we summarize various ways in which gene therapy can be combined with other therapies and highlight the role of nanoplatforms in mediating these combined therapies, which would inspire novel design ideas toward combination therapies. Additionally, bottlenecks and barriers to gene therapy should be addressed in the near future to achieve better clinical efficacy.

Keywords: combinational therapy, gene therapy, tumor treatment, nanoplatform, chemotherapy, phototherapy, magnetic hyperthermia therapy, immune therapy

1. Introduction

Cancer, a major public health problem worldwide, has tended to be the leading cause of death in the 21st century. According to the American Cancer Society estimates, nearly 600,000 people in the United States will die because of cancer in 2022.1 The number of Americans with cancer history is estimated to be more than 22.1 million in 2030 based on the growth and aging of the population alone.2 Chemotherapy, radiotherapy, and surgery are the main treatments for tumors, but their effects are not ideal for high mortality and side effects clinically. Meanwhile, tumor recurrence and metastasis are still a great challenge clinically, while there are no suitable therapeutics. After almost 30 years of development, gene therapy is becoming one of the most widely used therapeutic strategies except traditional therapies against cancers and can import healthy exogenous or therapeutic genes into host cells to kill cancer cells or protect normal cells.3 Several types of nucleic acid drugs were explored to heal cancer, such as Bcl-2 siRNA and suicide gene. Nucleic acid drugs can be divided into DNA and RNA, interfering with or regulating targeted gene expression in specific cells. Most types of DNA drugs target the cell nucleus, while RNA drugs target the cytoplasm. However, gene drugs can be easily degraded in vessels and into other organs; therefore, gene drugs are limited clinically.

The nanodrug delivery system provides an excellent platform for the delivery of gene drugs with its protective properties and targeted effects. Through rational design, nanomaterials can encapsulate nucleic acids effectively and protect gene drugs from degradation. Moreover, some types of nanomaterials could help gene drugs escape from lysosome and codelivery other drugs with nucleic acid. Many nanovectors are developed to deliver gene drugs, including liposomes, cationic polymers, etc. Nowadays, novel therapies are urgently needed for cancer treatments. Combining gene therapy with the currently available therapies such as chemotherapy or radiation therapy provides surprising hope for better therapeutic effects in patients with advanced-stage cancers. Nanovectors, which can load more drugs onto targeted organs and deliver them into the cytoplasm, perform excellently in combined gene therapy. Based on the therapeutic effect of gene delivery, we summarize the purpose and effects of gene therapy in combined therapy with a nanoplatform and the mechanism of combined therapy.

2. Gene Therapy for Tumors

2.1. Advantages of Gene Therapy

The main methods of gene therapy against cancer include using plasmid DNA containing therapeutic nucleotides to modulate aberrant gene expression and RNA interference like siRNA, shRNA, miRNA, and antisense oligonucleotide (ASO) to reduce cancer-related protein expression.4 Compared to conventional treatments, gene therapy offers a variety of advantages for cancer treatment, including high potency and specificity, low off-target toxicity, and delivery of multiple genes that concurrently target cancer tumorigenesis, recurrence, and drug resistance.5,6 As a powerful tool, genome editing technologies have been used widely in gene therapy for their properties of gene addition, gene ablation, and gene “correction” in vivo or in vitro, different from viral vectors that can only mediate gene addition.7 For example, adoptive cell therapy uses gene delivery to ex vivo modify the patient’s T cells to generate specific antitumor reactivity. It can improve the antitumor immune response in the body through artificial methods, achieving a sustained and strong antitumor effect. Until now, chimeric antigen receptor T cell (CAR-T) therapy, one of the adoptive cell therapies, has been developed to treat hematologic malignancies and multiple solid tumor types.8 Suicide gene therapy is based on introducing a suicide gene into specific tissue, such as a tumor, and triggering cell death by expressing specific enzymes, toxins, or pro-apoptotic proteins in tumor cells.9,10 It can enhance the sensitivity of tumor cells to chemotherapy and be controlled by a tumor-specific promoter to select expression in tumor cells.11

2.2. Current Challenges of Gene Therapy

There are many barriers inside and outside the cell for nucleic acid delivery. Naked nucleic acid can be easily degraded in blood for the presence of nucleases and has a very short half-time in physiological media. Once nucleic acid gets into a cell, it must escape from the lysosome or will be degraded in the lysosome. The tumor microenvironment (TME) can exhibit abnormal conditions, including hypoxia, low pH, and high reactive oxygen species (ROS) levels. Following single therapy, these conditions can promote cancer resistance, tumor aggressiveness, metastasis, and recurrence.

Moreover, some types of cells in tumor-like cancer stem cells (CSC), hypoxic cells, and S-phase cells have much more robust resistance to chemotherapy or radiation therapy, which tend to induce cancer recurrence or metastasis.12 For solid tumors, it is difficult for nucleic acid drugs to get into tumors and transfect target cells because of the complex compounds in solid tumors. The unfavorable physicochemical properties of nucleotides, such as negative charges, large molecular weight, and size, seriously hinder their entry into host cells. Meanwhile, clinical gene therapeutics are limited by the low stability of nucleotides induced by endonuclease in serum.12,13 Therapeutic nucleotides must overcome various biological barriers, from their entry into the bloodstream to their final destination in cancer cells to reach the cancerous site of action. For example, while injecting plasmid complex by intravenous injection, the gene complex should overcome the following biobarriers: (1) degradation by serum enzymes, (2) being removed by phagocytes and organs like kidney and liver, (3) crossing the vascular endothelial cells, (4) tumor microenvironment, (5) crossing the cellular membrane, (6) escape from endosome, and (7) crossing the karyotheca.13,14 Nanocarriers as promising tools could help nucleic acid drugs overcome the biobarriers mentioned above. Several types of nanocarriers could be stable in normal tissues and blood and degraded in tumors by the ligands or properties of nanomaterials. Other nanocarriers may help drugs cross vascular cells and escape from cell endosomes. There are some types of nanocarriers currently used for gene therapy, including liposomes, polymeric nanoparticles, dendrimers, and viral vectors. Liposomes are spherical vesicles made of phospholipids that can encapsulate and deliver DNA or RNA. Polymeric nanoparticles are made of polymers that can bind to nucleic acids. Dendrimers are highly branched, tree-like polymers that can encapsulate and deliver DNA or RNA. Viral vectors are genetically engineered viruses that can deliver therapeutic genes to cells. Each type of nanocarrier has its advantages and limitations, and researchers are continually working to improve their efficiency and safety, as well as exploring the development of novel nanocarriers.

3. Combined Gene Therapy with Other Cancer Therapies for Better Therapeutic Effect

Single therapies can hardly realize the desired therapeutic outcomes in clinical trials because of the unfavorable drug resistance and heterogeneity of tumors. Since then, synergistic combination therapies combining two or more therapeutic modalities have been receiving more and more attention. In cancer therapy, gene therapy is multifunctional, including the induction of cancer cell apoptosis, inhibition of tumorigenesis or metastasis, downregulation of heat shock proteins, and induction of immune response by expressing cytokines. Nowadays, it is becoming a strong complement to other cancer therapy. With the rapid development of nanometer material science, various nanomaterials with the ability to kill tumor cells and deliver gene drugs have been widely developed. These nanomaterials can use magnetic, luminous, or sound energy to kill cancer cells and deliver therapeutic nucleic acids like siRNA, ASOs, and so on to gain a much better therapeutic effect.

3.1. Combined Gene Therapy with Chemotherapy

Chemotherapy is the most common method of cancer treatment. The cell’s metabolism can be disturbed or interfered with by delivering chemical drugs into the cell, thus killing cells. However, chemotherapy is greatly limited by multidrug resistance, high drug dose concentration, low drug permeability, and adverse effects.15,16 To improve the antitumorigenicity, gene therapy is considered to supplement synergistic chemotherapy. Gene therapy works in conjunction with chemotherapy to increase the death of tumor cells or overcome the above-mentioned mechanisms and break the barriers to chemotherapy in the below ways (Figure 1A).

Figure 1.

Figure 1

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Synergistic therapeutic effect of chemotherapy and gene therapy. (A) Scheme of chemotherapy and gene therapy. (B) Nanocomplex could inhibit the expression of PIKM2, induce mitochondrial exhaustion and collapse, and enhance the cytoplasmic levels of cytochrome C. Reprinted with permission from ref (22). Copyright 2021, Elsevier B.V. (C) PAP could eliminate the tumor and suppress the expression of HIF-α. Reprinted with permission from ref (26). Copyright 2018, Elsevier B.V. (D) MDSCs were stained with CD11b and Gr-1 antibody and determined by flow cytometry. Reprinted with permission from ref (32). Copyright 2019, Elsevier B.V. (E) CCP/PCBP2 siRNA nanocomplex resulted in significant tumor inhibition via collagen expression. Reprinted with permission under a Creative Commons Attribution 4.0 International License from ref (36). Copyright 2021, Ivyspring International Publisher.

3.1.1. Synergistic Therapeutic Effect of Chemotherapy and Gene Therapy

By design of an intelligent drug delivery platform, chemotherapy and gene therapy can work together to heal cancer. Several gene medicines have been found and used in trials with chemotherapy treatment. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor family, can selectively induce cancer cell apoptosis by binding to the death receptor 4 (DR4), and DR5 is overexpressed in cancer cells.17 Besides, the TRAIL-based gene therapy produces the bystander effect to inhibit tumor growth in vivo.18 However, the following TRAIL-resistance of cancer cells undermines the TRAIL-based gene therapy.19 Human antigen R (HuR) is a potential cancer therapy target associated with tumorigenesis and metastasis. Amreddy et al. developed a folate receptor-α(FRA)-targeted polyamidoamine dendrimer-based nanoparticle system (Den-PEI-CDDP-siRNA-FA) for chemo/gene combined therapy.20 They used Den-PEI-CDDP-siRNA-FA to codeliver anti-HuR siRNA and cis-diamine platinum to treat FRA-overexpressing lung cancer cells. They gained a significantly more significant therapeutic effect than individual therapeutics. The enhanced mechanism of combined gene therapy with chemotherapy can be divided into the following content.

3.1.2. Fighting Multidrug Resistance in Treating Tumor

The use of chemotherapy, one of the most widely used and effective treatments for cancers, is seriously limited by multidrug resistance (MDR), which is developed by the continuous use of chemotherapy drugs. The cancer MDR requires an increasing dose of chemotherapy drugs, which could induce inevitable toxicity to patients. MDR is closely related to the overexpression of transporters like P-glycoprotein (P-gp) on the cancer cell membrane. Many drugs, such as doxorubicin (DOX) and paclitaxel (PTX), must enter the cells to play a therapeutic role. At the same time, P-gp, one of the ATP-binding cassette (ABC) transporters, can actively expel them out of the cells, reducing the efficacy.21 One of the strategies against cancer MDR is blocking out the energy supply for ATP-binding cassette (ABC) transporters, achieving a favorable therapeutic effect. A polyelectrolyte nanocomplex surface decorated with hyaluronic acid was developed to deliver DOX and PKM2 siRNA.22 The hyaluronic acid of the nanocomplex could target CD44, which is overexpressed in tumor cells, while the nanocomplex could efficiently escape from lysosomal entrapment and release siRNA into cells. By downregulation of PKM2, the energy supply for ABC transporters in cancer cells has been suppressed, thus defeating drug resistance. Results showed that combined therapy could enhance and decrease the expression of PKM2, induce mitochondrial exhaustion and collapse, and release cytochrome C into the cytoplasm (Figure 1B). Another mechanism of MDR is overexpressing growth factors in cancer cells.23 RNase-resistant RNA nanoparticles are modified with an epidermal growth factor receptor (EGFR) to block the growth factor signing pathway. Targeting aptamer loading XBP1 siRNA, which could promote sensitization to chemotherapy and impede angiogenesis in vivo, was developed to kill cancer cells and inhibit tumor growth.24 Hypoxia is a hallmark feature of the tumor microenvironment, which could inhibit the efficiency of chemotherapy.25 The aim is to reduce hypoxia’s influence, a novel multifunctional hypoxia-induced size-shrinkable nanoparticle designed to codelivery DOX and si-HIF1α.26 The nanoparticle could respond to hypoxia and degrade the outer PEG to expose positively charged PAMAM, thus penetrating DOX and si-HIF1α into the tumor core. The expression of HIF1α induced by hypoxia is downregulated by si-HIF1α, which ultimately enhances the effectiveness of DOX in treating cancer (Figure 1C).

3.1.3. Restoring Homeostatic Stromal Function to Promote Therapeutic Efficiency and Drug Delivery

Besides the MDR of cancer cells, tumor stroma also plays an important role in drug resistance.27 To delay the MDR progression, optimized combined treatments are badly needed.28 The tumor-associated macrophages (TAMs) contribute to drug resistance and relapse via different pathways and are major components of the tumor microenvironment.29 The hyaluronic acid-based nanoparticles were designed to encapsulate miR-125b (HA-PEI-miR-125b), which can specifically target TAMs and repolarize macrophages to an immune-activating phenotype. Results show that the total number of CD11b+, F4/80+, and CD206+ macrophages was reduced while increasing the number of CD80+ macrophages. However, there is no obvious difference of CD45+ immune cells between the untreated control and HA-PEI-miR-125b treated group, and whether the nanoparticle could increase the number of PD-1+ immune cells by increased infiltrating T cells needs further evaluation. Later results show that HA-PEI-miR-125b could enhance the efficacy of paclitaxel with low toxicity.30 Myeloid-derived suppressor cells (MDSC) are largely immature myeloid cells that inhibit immune effector cell function in cancer and tumor progression, representing a potential therapeutic target for cancer therapy.31 A multifunctional delivery system based on an amphiphilic polymer with morpholine attached to the pendant side chains (POEG-st-Pmor) for codelivery of IL-36γ expression plasmid and doxorubicin (DOX) has been developed to treat cancer. The nanomicelles are stabilized by charge–charge interactions between the cationic polymer and plasmid DNA, which are further addressed in vivo. The Dox+IL-36γ/POEG-st-Pmor decreases the MDSC in the lung metastasis of breast cancer and hence enhances the type I immune response, which raises the efficiency of DOX (Figure 1D).32

One of the main difficulties in treating tumors such as pancreatic cancer is the nearly impenetrable desmoplastic stroma. It prevents drugs into tumors and supports and promotes pancreatic cancer at the same time.33,34 One strategy to achieving more drugs into stroma-rich tumors is restoring homeostatic stromal function. A gene-/chemo-combined strategy was developed.35 The PEGylated PEI-coated gold NPs were developed to codeliver anti-HSP47 siRNA and ATRA to transform activated pancreatic stellate cells into quiescent pancreatic stellate cells, which could promote gemcitabine delivery into a pancreatic tumor. A peptide-based core-stabilized PCBP2 siRNA nanocomplex was developed to break type I collagen in pancreatic ductal adenocarcinoma (PDAC) tumor stroma (Figure 1E).36 After siRNA reverses the accumulation of type I collagen, the antitumor efficacy of gemcitabine was significantly improved. Cancer-associated fibroblasts could secret a dense desmoplastic matrix or release regulatory molecules, thus enhancing chemotherapy resistance.37 Blocking collagen cross-linking and fibronectin fibril assembly via lysyl oxidase (LOX)-siRNA could enhance doxorubicin sensitization against the triple-negative breast cancer (TNBC) cell, indicating that combining DOX with LOX siRNA is a promising therapeutic method.38

While chemotherapy is a commonly used method for treating cancer, it has limitations such as multidrug resistance, high drug doses, low drug permeability, and adverse effects. However, gene therapy can be used with chemotherapy to increase the death of tumor cells or overcome these limitations. By the design of intelligent nanomaterials, the synergistic therapeutic effect of chemotherapy and gene therapy can be achieved in two ways. One way is to combat multidrug resistance in tumors by disrupting gene expression within the tumor cells. Another way is by restoring the homeostatic stromal function, which can also promote therapeutic efficiency and drug delivery. Finally, a combined gene/chemo strategy can effectively treat tumors.

3.2. Combined Gene Therapy with Phototherapy

Phototherapy can be divided into two main categories: photothermal therapy (PTT) and photodynamic therapy (PDT). PTT is a widely developed localized cancer therapy that utilizes photoinduced heat via near-infrared irradiation to cause cancer cell death and avoid damage to other regions which are not irradiated.39−41 Compared to traditional therapies, the main advantages of PTT are minimal invasiveness, deep tissue penetration, and simple operation.40,42 Another promising cancer therapy based on photosensitizer (PS) is PDT, which uses visible light to irradiate PS to generate ROS, thereby killing cells.40 PDT is a good choice for clinical cancer treatment, particularly for superficial tumors like esophageal, bladder cancer, and melanoma, because of its eximious features such as low invasiveness, mild killing, spatiotemporal selectivity, and lower side effects.43,44 One of the most significant advantages of phototherapy is its ability to control drug release achieved by visible or infrared light. However, for those metastatic or disseminated cancers, a single PTT or PDT appears powerless.45

Currently, gene therapy is an effective complement to PTT/PDT because of its superiority in therapeutic enhancement and decreasing side effects.46−49 Therapeutic nucleic acids, such as siRNA, have been widely used to combine PTT/PDT to gain a synergistic therapeutic effect. The synergistic effect of gene therapy and PTT is mainly achieved in two ways. Either gene therapy and PTT kill tumor cells together, in which gene therapy can kill the surrounding or PTT-resistant tumor cells, or gene therapy can improve the sensitivity of tumor cells to PTT, such as inhibiting the expression of heat shock proteins from improving the efficacy of PTT. Several inorganic materials have been applied in gene/photothermal combined therapy, such as gold nanoparticles (GNs), black phosphorus nanosheets (BP NS), carbon-based materials, and others.39,50,51 Some inorganic nanomaterials cannot be loaded with therapeutic nucleic acids, so modification of these materials is needed, such as cationic polymer modification on the material’s surface to load the nucleic acid by electrostatic interaction between the cationic polymer and the nucleic acid.41

3.2.1. Synergistic Therapeutic Effect of Phototherapy and Gene Therapy

The most widely used strategy for gene therapy combined with PTT/PDT is the synergistic method for utilizing antitumor genes with PS together (Figure 2A). Survivin, a member of the inhibitor of apoptosis (IAP) families, is overexpressed in most human tumors and is considered an excellent target for cancer gene therapy.52,53 Metal–organic nanostructures (MONs) have significant advantages in combination therapies for traditional photosensitizers like indocyanine green (ICG) with therapeutic nucleotide.49,54 The Zn(II)-dipicolylamine (Zn-DPA) molecule is a potential siRNA delivery carrier, because of its high affinity for phosphate-containing molecules. Gold nanorods (GNRs) conjugated with Zn-DPA were designed to deliver PLK1-siRNA and PTT simultaneously. They found that the combination of PLK silencing-induced apoptosis and local PTT had apparent synergy for treating PC-3 tumor.46 A coordination-driven self-assembly MONs have been developed for gene/photothermal combined therapy.49 The Zn(II)-dipicolylamine (Zn-DPA) molecule interacted with ICG and polyvinylpyrrolidone (PVP) polymers to form nanoICG, which was modified with RGD, one of the peptide motifs targeting angiogenesis. Due to the high siRNA transfection, long-lasting tumor accumulation, and good photothermal properties, the R-nanoICG binding with survivin-siRNA presented apparent synergistic efficacy of PTT and gene therapy. The angiogenesis assay showed that the PTT/gene therapy group had the lowest level of CD31, which indicated that combination therapy had the most efficiency for destroying tumor blood vessels (Figure 2B). In the 4T1 xenograft mouse model, the tumors were entirely eliminated after combination therapy treatment, while the tumors could not be inhibited by a single therapy.

Figure 2.

Figure 2

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Synergistic therapeutic effect of phototherapy and gene therapy. (A) Scheme of phototherapy and gene therapy. (B) R-nano ICG/S-siRNA could destroy tumor blood vessels and increase tumor temperature. Mice injected with PBS (1), ICG (2), nanoICG (3), R-nanoICG (4), and R-nanoICG/S-siRNA (5) and irradiated with an 808 nm laser at a power density of 1.0 W cm–2. Reprinted with permission from ref (49). Copyright 2018, Wiley-VCH. (C) Representative noninvasive imaging of lung-adenocarcinoma NCI-H889 tumor-bearing nude mice with different treatments at days 7 and 36 and immunohistochemical analysis of VEGF in lung tissue. Reprinted with permission under a Creative Commons Attribution 4.0 International License from ref (60). Copyright 2021, Springer Nature. (D, E) DOX-siVEGF-NPs/Ce6-MBs generate more ROS with laser and inhibit tumor growth. Reprinted with permission from ref (80). Copyright 2020, Elsevier B.V. (F, G) PEG and PEI dual-functionalized BP nanosheets could target tumor sites and induce cell death. Reprinted with permission from ref (86). Copyright 2018, American Chemical Society.

BP NS, a kind of attractive two-dimensional (2D) material with photodegradable character, high surface area, and negative charge, has high photothermal conversion efficiency and significant extinction coefficient, considered a good nanomaterial for PTT.39,55,56 Moreover, BP NS has been efficient PTT therapy agents for anticancer treatment because of its ability to generate singlet oxygen (1O2) with a high quantum yield of ∼0.91 under the whole range of visible light.56 In 2018, Wang et al. first utilized BP NS for gene-/PTT-combined therapy and reported it was a promising tool for combined therapy.57 The negatively charged BP NS was modified with PEI, which enabled it to be loaded with survivin-siRNA. The results of the Western blot showed that the expression level of survival in MCF-7 cells (breast cancer cells) was significantly decreased by being treated with BP-PEI-siRNA for 24 h, which could inhibit cell growth (44% inhibition rate). With simple design, the BP nanosheets could degrade into phosphate ions in vivo, which indicates that the BP-PEI-siRNA complex could be a promising tool for clinical applications.

Furthermore, the inhibition rate of MCF-7 cells increased to 64% when the cells were treated with BP-PEI-siRNA for 24 h and 1.0 W cm–2 808 nm irradiation for 10 min. In in vivo tumor of MCF-7 cells, the combination of BP-PEI-siRNA with 808 nm irradiation had the most potent inhibition of tumor growth, indicating antisurvivin gene therapy and PTT of BP-PEI-siRNA had more effective than single therapy. Gold nanomaterials, the most widely applicable multifunctional agents in PTT, are usually used in combined therapies based on their versatile surface chemistry.48,51,58 Using gold nanomaterials, a more effective therapeutic could be achieved. A gold nanorod was modified by the TAT peptide and thiolated DNA linker to deliver the sgRNA/Cas9 complex, which silenced the tumor-associated gene PLK1.59 A significant inhibiting effect was observed after mild photothermal therapy combined with gene therapy. A gold nanocage vehicle loading DOX and siRNA was modified with the AS1411 aptamer for the combination of tumor-responsive genetic therapy, chemotherapy, and photothermal treatment.60 As shown in Figure 2C, a pronounced decrease of VEGF and fewer tumor foci were seen in the Au-siRNA-PAA-AS1411 group, which was treated with a combination of tumor-responsive genetic therapy, chemotherapy, and photothermal treatment. By designing the ROS-responsive materials, NIR spatially activated siRNA therapy can be achieved to treat tumor sites with PDT therapy.61 In normal tissue, siRNA molecules cannot function due to being trapped and broken down in endolysosomes. This is caused by the quaternary ammonium moiety’s unprotonatable property, keeping the siRNA in an “off” state. However, when NIR irradiation is applied to tumor tissue, it triggers the release of siRNA from the endolysosomes and into the cytosol. This is achieved through the cleavage of TK bonds and the photochemical internalization effect, resulting in the “on” state of siRNA activity. By inhibiting the glutathione peroxidase 4 gene, siRNA enhances the accumulation of ROS, which synergizes with Ce6 photodynamic therapy to provide effective antitumor activity in vivo. This is achieved through ROS-sensitive cationic nanocarriers, which provide a feasible and controlled strategy for delivering siRNA therapy with synergistic drug effects specific to tumors. The enhanced mechanism of combining gene therapy with phototherapy can be divided in the following ways.

3.2.2. Increasing the Efficacy of Phototherapy

The increased thermotolerance induced mainly by the upregulation of heat shock proteins (HSPs) is the main reason for the failure of PTT.62 HSPs can act as ATP-mediated molecular chaperones to correct proteins’ misfolding, thereby keeping their activities under hyperthermia.62,63 For thermotolerance in many cancer cells, HSP70 and HSP90 are crucial proteins.63,64 Applying siRNA against the HSP family can improve cells’ sensitivity to PTT and enhance the efficiency of PTT.58,63,65

Bcl-2-associated athanogene domain 3 (BAG3), acting as a molecular cochaperone of the HSP family, including HSP70, is also an antiapoptotic protein.66−68 The evidence showed that the BAG3 overexpression was closely related to the tolerance of PTT, radiation therapy, and chemotherapy.69 The combination of BAG3-siRNA and gold nanorods (GNRs) in gene and photothermal therapy was studied. Treating GNRs-mediated PTT can significantly increase the expression of BAG3 and HSP families (HSP27, HSP60, HSP70, and HSP90) in Cal-27 cells, which indicates the PTT-induced heat shock response. However, applying BAG3-siRNA could significantly inhibit the heat shock response, which could strengthen cells’ sensitivity to PTT. The GNRs-siBAG3 complex showed a stronger BAG3 silencing capability than lipofectamine 2000-siBAG3 and a higher efficiency of PTT than GNRs themselves, which completely suppressed the growth of Cal-27 tumors in vivo.

The generation of HSPs after PTT relies on an abundant ATP-meditated energy metabolism.70 Therefore, weakening the energy metabolism seems to be a potential solution to downregulate HSPs expression during PTT.65 Pyruvate kinase M2 (PKM2) is involved in ATP production in cancer cells.71 In recent work, a combined strategy of gene therapy and PTT was reported.64 Simply put, the spherical dendrimer-polypeptide (DPP) was synthesized through the PAMAM-mediated ring-opening polymerization of N-carboxy anhydride. Then, DPP was used to load ICG and PKM2-siRNA and finally was coated with human serum albumin. Compared to commercial transfection reagents (25 kDa PEI and Lipofectamine 2000), DPP had a dramatically more substantial cellular uptake capacity and a higher PKM2 silencing efficiency (∼87%) in MCF-7 cells. Both qPCR and Western blot in vivo and in vitro showed the same results: the inhibition of PKM2 expression could remarkably inhibit the production of HSP70 and HSP90 due to the lack of ATP. The triple synergy of siPKM2-induced cell starvation, downregulated HSP expression, and PTT showed surprisingly anticancer efficacy for in vivo MCF-7 xenograft model. The tumors of the combined therapy group were completely suppressed within the observation period, and the survival rate of the combined therapy group was satisfactorily 100% within the observation period of 50 days, which is significantly higher than those of other groups.

The local PTT inevitably induces the heat damage of surrounded normal cells, which is likely to cause cancer cell metastasis and local inflammation.72−74 Low-temperature PTT seems an excellent choice to avoid the side effects because it relies on low-temperature heat-induced cellular apoptosis.72,75,76 The efficacy of low-temperature PTT to solid tumors is still undesirable due to increased thermotolerance induced by upregulated expression of intracellular HSPs.77,78 A general strategy was investigated for combining low-temperature PTT and gene therapy against HSP70.63 First, a siRNA-bearing self-assembled nucleic acid nanogel based on nucleic acid hybridization between DNA-grafted polycaprolactone (DNA-g-PCL) and siRNA linker was developed.79 The siRNA-bearing nucleic acid nanogel was coated with polydopamine and surface PEGylated, named PP-NG. The in vivo efficacy of PP-NG-siHSP70 combined with low-temperature PTT was then evaluated on HeLa tumor xenografts.

Furthermore, the Hela tumor growth was almost completely suppressed under the treatment of PP-NG-siHSP70 (laser), and more surprisingly, two-thirds of the tumors completely disappeared. Moreover, PP-NG-siHSP70 plus laser could induce the most effective inhibition of HSP70 expression and increase the level of caspase-3 expression. This triple-shield complex PP-NG-siHSP70 showed the capability of strongly ablating solid tumors under mild conditions. Further, this gene delivery system could be expanded to other combined therapies such as gene/photothermal/immune combined therapy.63

PDT could be strengthened by downregulating the selected gene. Recently, chemophotodynamic combination therapy has become an ideal strategy. However, tumor cells treated by PDT will induce an abnormal increase in angiogenesis for generating reactive oxygen species (ROS). A complex composed of two compartments was developed to suppress tumor angiogenesis.80 The first compartment is nanoparticle loading DOX and siRNA silencing the VEGF gene, while the other part is a Ce6-encapsulating microbubble. Three therapies showed significantly lower tumor growth, indicating that overexpression of VEGF was successfully prevented, and further angiogenesis was restrained (Figure 2D and E). Survivin, an antiapoptosis protein, was overexpressed in tumor cells after treatment, thus leading to therapeutic resistance in tumors.81,82 To downregulate the survival level in cancer cells, Jin et al. designed an upconversion nanoplatform for enhanced PDT.83 They used upconversion nanoparticles adsorbing a long single-stranded DNA (ssDNA) with multiple copies of the aptamer (AS1411) and DNAzyme to specifically target nucleolin overexpressed on cancer cells specifically. The AS1411 aptamer could encapsulate the photosensitizer 5,10,15,20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4) as well as recognize the nucleolin overexpressed in tumor. The upconversion nanoplatform could trigger PDT not only under NIR light but also with high recognition and loading capacity. The combined therapy dramatically silences surviving gene expression, hence enhancing the efficiency of PDT.

3.2.3. Inhibiting Growth and Metastasis of Tumor Cells to Assist PDT/PTT in Treatment of Tumors

Cancer metastasis is the leading cause of tumor recurrence. Though some single therapies like PTT,84 PDT, MHT, and sonodynamic therapy (SDT) have been considered promising therapies because of their stable spatiotemporal control, they are designed as localized anticancer treatments that are powerless against the cancers that transfer or survive after treatment.40,43

Human telomerase reverses transcriptase (hTERT) is closely related to cancer metastasis and growth.85 A dual-functionalized BP NS modified with poly(ethylene glycol) (PEG) and PEI (PPBP) was designed to deliver hTERT siRNA for gene/photodynamic/photothermal combination therapy.86 Through the detection of the degradation of PPBP under different conditions, it is found that PPBP degrades more significantly under a combination treatment of H2O2 and PBS of pH 5.0, compared with a single treatment of H2O2 or PBS of pH 5.0, indicating PPBP can be specifically degraded in the microenvironment of acidic lysosome and high photoinduced ROS. si-hTERT synergizes with PDT and PTT on Hela cells. Moreover, results showed that the introduction of si-hTERT can effectively cooperate with PTT/PDT therapy to inhibit the metastasis and growth of A549 cells in vivo through downregulating hTERT (Figure 2F and 2G).86

As described above, the TRAIL gene has been used wildly in gene therapy. Single gene therapy will lead to uncontrollable expression of TRAIL in vivo, which phototherapy could solve for its property of controlled drug release. Meanwhile, the recurrence of tumor cells after PTT could be killed by TRAIL treatment. For example, Qiao et al. developed semiconducting nanoparticles decorated with caged TRAIL-expressing plasmid under HSP70 protomer named SPN@HSP70-TRAIL-GFP(SPNHT).87 SPNHT has great potential to induce cell apoptosis in vitro and in vivo with a laser, indicating that combined therapy could effectively restrain tumor recurrence after PTT treatment.

3.2.4. Protecting Normal Cells and Reducing the Toxicity of PTT/PDT

The traditional treatment and some other new therapies like PTT and PDT have high antitumor efficiency, but at the same time, they are likely to be harmful to normal healthy cells.88 As two significant photo sources are used in phototherapy, short-wavelength UV/visible light cannot penetrate deeply into tissue. At the same time, high-power-density near-infrared (NIR) light can cause undesired heat damage. To solve this problem, a ROS-degradable polycation was designed to codeliver a photosensitizer (PS) and gene drug, which uses far-red light (661 nm) at low optical power density.89 The polycation could release the P53 gene under exposure to far-red light and work together with ROS to induce the death of cells.

In most cases, HSP can be an unfavorable factor during phototherapy. However, utilizing this property can also be an excellent way to take control of gene expression. A multifunctional nanocomposite named PBDTQ, which loads a plasmid inserted CD-TK double suicide gene with HSP70 promoter, could achieve heat-controlled gene expression.90 Furthermore, the suicide gene expression of cytosine deaminase (CD) and herpes simplex virus type-I thymidine kinase (TK) could turn prodrugs, 5-fluorocytosine (5-FC) and ganciclovir (GCV), loaded in PBDTQ into their cytotoxic forms of 5-fluorouracil (5-Fu) and ganciclovir-triphosphate (GCV-TP) to minimize collateral damage and nontargeted side effect.

In summary, gene therapy is an effective complement to phototherapy as it enhances therapeutic efficacy and reduces side effects. For metastatic cancers, a single PTT or PDT may not be effective. Gene therapy, specifically the use of a therapeutic nucleic acid such as siRNA, has been widely used to combine with PTT/PDT to gain a synergistic therapeutic effect. The synergistic effect of gene therapy and PTT is achieved in two ways: either they kill tumor cells together, or gene therapy can improve the sensitivity of tumor cells to PTT, such as by inhibiting the expression of heat shock proteins. The inhibition of tumor growth and metastasis is also possible with the combination of gene therapy and phototherapy. To reduce the toxicity of phototherapy, far-red light at low optical power density can be used, and gene expression can be controlled by utilizing the properties of heat shock proteins.

3.3. Combined Gene Therapy with Magnetic Hyperthermia Therapy/Magnetothermal Therapy

Magnetic hyperthermia therapy (MHT), another kind of promising hyperthermia therapy for localized treatment of solid cancer, utilizes an external alternating magnetic field (AMF) to selectively heat magnetic nanoparticles (MNPs or MNs), inducing tumor cell death/apoptosis.91 Magnetic particle imaging (MPI) can help track the MNPs’ delivery and carefully control the release of drugs.92 Due to its safety, high efficacy, and excellent tissue penetration, MHT has entered the clinical trial stage (ClinicalTrials.gov Identifier: NCT02033447). In order to be clinically applicable, the temperature of MHT (43–46 °C) and the accumulation of MNPs in tissue must be strictly controlled.93 However, since the frequency f and field amplitude H of AMF (f × H < 5 × 109 Am–1s–1) is strictly limited by technology and biomedical reasons and the thermal conversion efficiency of the existing MNPs is unable to meet the satisfaction, the therapeutic efficacy of single MHT is still limited and unsatisfactory.94−96 Hence, many combined strategies are developed to enhance the efficacy of MHT, such as PTT/MHT, PDT/MHT, chemotherapy/MHT, gene therapy/MHT, and so on.94 In order to achieve codelivery of heat magnetic nanoparticles and gene drugs, there are three main strategies as following: delivering MNPs and therapeutic oligonucleotide separately; modifying the surface of MNPs with gene vectors like cationic polymers which are able to load negative oligonucleotide; using MNPs themselves to load pDNA/polymer complex.97−99

It was reported that a mild multiple MHT-mediated TRAIL release system was a good solution for TRAIL-resistant cancer cells. A biodegradable TRAIL/SPION nanocomplex hydrogel (T/S-NH) designed for combined therapy with MHT and simultaneously MHT-induced TRAIL release.100

3.3.1. Synergistic Therapeutic Effect of MHT and Gene Therapy

The unique magnetism gives MNPs enhanced cellular internalization, controllable tumor accumulation under external magnetic fields, and control of target gene expression under AMF (Figure 3A). Through multiple surface modifications of viral or nonviral vectors, MNPs can load therapeutic nucleotides to achieve the combined gene/magnetic hyperthermia therapy.101 In the earliest examples of the combined therapy, they injected 20 μg of pGadTNF into tumors by a lipofection method for TNF-α gene therapy and, after 1 day, injected magnetite cationic liposomes into tumors for MHT under AMF (118 kHz and 30.6 kA/m) for 30 min. The hyperthermia (46 °C) and overexpression of TNF-α (3-fold vs control group) resulted in potent inhibition of U251-SP tumor growth (0.5 ± 0.4 cm3 on day 32), which was significantly smaller than that of single MHT (2.0 ± 1.1 cm3 on day 32) or TNF-α gene therapy (2.9 ± 1.1 cm3 on day 32).98

Figure 3.

Figure 3

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Synergistic therapeutic effect of MHT and gene therapy. (A) Scheme of magnetic hyperthermia therapy and gene therapy. (B) The shape of differently shaped M-MSNs, plots of inverse transverse relaxation time (1/T2) versus Fe concentration of the M-MSNs, and photographs of HepG2 tumor-bearing mice in each group and MR images of mice from different groups at day 7 and 14 after treatment (tumors marked by the white arrow). Reprinted with permission from ref (104). Copyright 2018, Elsevier B.V. (C) The effects of let-7a gene and FACS analysis of combination-treated cells compared to controls. Reprinted with permission from ref (109). Copyright 2014, Wiley-VCH. (D) RT-PCR demonstrating the successful synthesis of the sTRAIL-EGFP plasmid transfected into A2780 ovarian cancer cells, and tumor volume was followed over 2 weeks. The size of the tumors decreased significantly when treated with the engineered AD-MSCs. Reprinted with permission from ref (110). Copyright 2016, Elsevier B.V.

Among the numerous gene therapy clinical trials, the herpes simplex virus thymidine kinase (HSV-TK) gene is the best-characterized suicide gene for tumor cell killing. The HSV-TK can make nontoxic ganciclovir monophosphate into toxic ganciclovir triphosphate, leading to a bystander effect.102 Here 25 kDa PEI-Fe3O4 MNs were developed to deliver the HSV-TK suicide gene induced by an α-fetoprotein promoter and hypoxia enhancement for the combined gene/magnetic hyperthermia therapy of hepatocellular carcinoma (HCC). They found a synergistic therapeutic effect of the combined therapy.103 Sphere-like and rod-like shape-controlled magnetic mesoporous silica nanoparticles (M-MSNs) were developed to integrate gene therapy, MHT, and magnetic resonance imaging together.104 Modified with PEG-g-PLL, the positively charged M-MSNs were used to load ganciclovir and the HSV-TK plasmid. Both shapes of M-MSNs with ganciclovir and pTK demonstrated a highly effective combined suicide gene/magnetic hyperthermia therapy of HCC (Figure 3B). Compared to sphere-like M-MSNs, rod-like M-MSNs showed higher magnetic targeting and combined therapeutic performance (90% inhibition in vivo). Gene therapy could enhance the effect of MHT in several ways, as described below.

3.3.2. Improving the Sensitivity of Tumor Cells to MHT

Gene therapy, as an exciting tumor treatment, can improve the sensitivity of tumor cells to hyperthermia induced by MHT by regulating heat resistance-related genes like HSPs. The inhibition of HSPs expression makes it possible for a practical therapeutic effect of magnetic nanoparticle complex under mild heating or low concentration, which can decrease the risk of inflammation and damage to surrounding normal cells.105 In Court et al.’s study, they detected the gene expression of ovarian cancer cell line HeyA8 cells after treatment of MHT (43 °C, 30 min) through microarray analysis and found that the top 20 upregulated genes contained HSP70 (HSPA6, HSPA7, HSPA4L) and BAG3.106 Then, they investigated the combination of HSPA6-siRNA and MHT to treat ovarian cancer cells in vitro and in vivo. Four kinds of anti-HSPA6 siRNA were selected to inhibit HSPA6 expression in ovarian cancer cells (A27880 cP20 and HeyA8), and all four HSPA6-siRNA-showed a noticeable improvement to CMDx-IO based MHT in vitro. The similar positive impact of HSPA6-siRNA on MHT was verified in an in vivo subcutaneous ovarian tumor model.

Besides siRNA therapy, micro-RNAs are reported to combine with MHT against HSP. Compared to the gene therapy based on siRNA, which only modulates single HSP-related targets, the gene therapy based on miRNA can modulate multiple targets on the same or similar pathways, indicating a more significant and broader effect.107 Lethal-7a miRNA (let-7a), a tumor suppressor, is downregulated in several human cancers, including brain cancers. Let-7a is associated with DNA repair and cell survival mechanisms by targeting factors such as RAS, MYC, and cyclin D, also related to downstream regulation of the HSP family.108 The combined therapy of miRNA gene therapy with ZnFe2O4-based MHT was developed.109 The negatively charged ZnFe2O4 MNPs were modified with 10 kDa branched PEI to load let-7a miRNA through a two-step layer-by-layer process. To evaluate the therapeutic enhancement of let-7a to MHT, U87-EGFRvIII cells were treated with let-7a, magnetic hyperthermia, or the combination. The combined treatment group exhibited lower cell viability (34%) than the single treatment groups (let-7a treatment 68.9%, magnetic hyperthermia 63.14%). A mechanistic study of combined therapy showed the upregulation of caspase-3 and downregulation of PI3K, HSPs (HSP27, HSP70, HSP72, and HSP90), and let-7a targets (RAS, MYC, and IGF1R), which suggested that let-7a could enhance the MHT to glioblastoma multiforme through inducing cell apoptosis and increasing the sensitivity of cells to magnetic hyperthermia (Figure 3C). The MNPs can be further modified with targeting ligands or PEG to improve the targeting and biocompatibility.

Nevertheless, due to the limitations of magnetic materials and gene vectors, the combination of gene therapy and MHT still receives less attention. The development of the combined therapy should consider the rational combination of MNs, surface decorations, nucleic acid types, and genes. Recently, magnetic hyperthermia-mediated gene therapy has been receiving increased attention. In this gene therapy, MNs enhance tumor accumulation, therapeutic gene release, and magnetic hyperthermia-activated gene expression.101 For example, a novel mild magnetic hyperthermia-activated stem cell-based gene therapy was developed to heal ovarian cancer. Here, 25 kDa PEI-modified magnetic core–shell nanoparticles composd a ZnFe2O4 core and mesoporous silica shell to deliver and activate heat-inducible TRAIL plasmid with HSP70 B’ promoter in mesenchymal stem cells.110 MCNPs can deliver a heat-inducible plasmid encoding TRAIL and activate TRAIL secretion in engineered AD-MSCs with mild magnetic hyperthermia. Quantifying luminescence intensity shows that the engineered AD-MSCs are significantly better than treatment with a single dose of recombinant TRAIL (Figure 3D).

In short, gene therapy can improve the sensitivity of tumor cells to hyperthermia induced by MHT by regulating heat resistance-related genes like HSPs. The inhibition of HSPs expression makes it possible for a practical therapeutic effect of magnetic nanoparticle complexes under mild heating or low concentration, which can decrease the risk of inflammation and damage to surrounding normal cells. Various studies have reported that combined therapy has shown significant and broader effects compared to single therapy. Meanwhile, the development of combined therapy should consider the rational combination of MNs, surface decorations, nucleic acid types, and genes.

3.4. Combined Gene Therapy with Immune therapy

The immune system is the key to detecting and eradicating cancer cells in vivo, involving a series of complex mechanisms. On the one hand, it can effectively prevent the occurrence and development of malignant tumors. However, on the other hand, it will also promote the selection of immune-tolerant tumor cells. After three stages of tumor development (elimination, equilibrium, and escape), tumors in the body have evolved into tumor cells that can evade the immune response, resulting in uncontrollable cancer in the body.111 The immune system has been considered to be a key point for cancer healing and detection. Immune cells can be engaged in a battle with cancer cells. Other cases can promote the metastasis and recurrence of tumors after three phases of eliminating, balancing, and escaping tumor cells, which involve complex mechanisms. The mechanisms for the escape of cancer cells from the immune system have been widely studied, including the change of immune checkpoint proteins like PD-1, and CTLA-4, manipulation of cytokine expression, and alteration of antigens.111,112 Newer therapies combined with gene therapy and immunotherapy have flourished in recent years and made encouraging progress, including OV therapy, adoptive immunotherapy, and tumor vaccine. Besides, certain materials exhibit immunomodulatory effects that can potentially synergize with gene therapy drugs to enhance their efficacy.113

3.4.1. Synergistic Therapeutic Effect of Immunotherapy and Gene therapy

Immunotherapy is a promising therapeutic that has been investigated widely in recent years. The main types of cellular immunotherapy include CAR T, TCR-transduced T cells (TCR-T), tumor-infiltrating lymphocytes (TIL), and natural killer (NK) cells. CAR T therapy is a hot field in clinical practice. Five cell therapies approved by the U.S. Food and Drug Administration (FDA) come from this field. Checkpoint inhibitors (ICI) have revolutionized cancer treatment and have become the standard of care for many cancer patients. Although immunotherapy has been applied in terminal cancer, it is greatly limited by an immunosuppressive tumor microenvironment for low pH, hypoxia, etc. Gene therapy could steadily activate immune cells in the tumor microenvironment or enhance the vaccine effect, thus gaining the strengthening therapeutic effect (Figure 4A).

Figure 4.

Figure 4

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Synergistic therapeutic effect of immunotherapy and gene therapy. (A) Scheme of immunotherapy and gene therapy. (B) Western blotting of OVA proteins in RAW264.7 and DC2.4, showing the expression of OVA in GLP-O and GLP-RONP groups and H&E images of lung tissues collected on day 40, showing that the GLP-RO Gel could efficiently prevent the formation of metastasis. Reprinted with permission from ref (118). Copyright 2021, American Chemical Society. (C) The polarization states of macrophages stimulated with supernatants derived from transfected B16F10 cells were assessed by FCM. The PD-L1 expression levels in tumors subjected to different treatments were assessed by FCM. Codelivery of CCL19 pDNA and BMS-1 in RGD-DMA nanoparticles reshaped the TME and significantly inhibited the abdominal dissemination of cancer. Reprinted with permission from ref (121). Copyright 2021, Wiley-VCH. (D) Immunohistochemical images showing the expression of PD-L1 (brown) in CT26 tumor tissue. Red arrows indicate PD-L1 protein. Western blot analysis of PD-L1 expression in CT26 tumor tissue collected from mice in the indicated treatment groups and Statistical analysis of the number of TUNEL+ cells per field for B16 and CT26 tumor. Scale bar = 50 μm. Reprinted with permission from ref (123). Copyright 2020, American Chemical Society.

3.4.2. Using an Oncolytic Virus to Combat Tumors

Immunity therapy is usually combined with oncolytic virus therapy because oncolytic virus (OVs) could induce immunogenic cell death, release tumor-associated antigens (TAAs), disrupt immunosuppression within tumors, and promote antitumor immune responses.114 The Phase I study of Delta-24-RGD oncolytic adenovirus showed a significant antitumor efficiency because of a direct oncolytic effect and a following antitumor immune response.115 The oncolytic virus/immune combined therapies of Delta-24-RGD and anti-PD-1 antibodies are undergoing Phase II clinical trials (ClinicalTrials.gov identifier: NCT02798406). Through modifying antitumor cytokine or antiviral cytokine genes, oncolytic virus therapy combined with gene therapy can improve the relative dismal efficacy of a single oncolytic virus agent or reduce the virus-induced toxicity. Amgen’s T-Vec (talimogene laherparepvec), the first approved oncolytic virus by FDA, was modified with the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) gene and gained a highly therapeutic effect in melanoma patients with a durable response rate of 16% in advanced melanoma patients to 2% in the control group.116 Stephen Russell at Mayo Clinic developed a recombinant oncolytic vesicular stomatitis virus (VSV) expressing the antiviral cytokine interferon-β to protect noncancerous cells from being killed.116,117 However, the immune response induced by OVs or the cytokines expressed by OVs is likely to be systemic, increasing the risk of OVs’ toxicity. A modified oncolytic adenovirus Delta-24-RGDOX was developed to express an immune costimulatory OX40L (OX40 ligand) which can bind a unique costimulatory OX40 on the T cell membrane and help T cells to recognize TAAs. The treatment induced complete regression in the long term surviving mice treated with the combination. Combining OX, immune therapy, and the unique gene OX40L gave Delta-24-RGDOX a specific immune response to cancer cells, significantly reducing the potential immunotoxicity of OVs.114

3.4.3. Nucleic Acid-Based Vaccine

Nanovaccine is a new therapeutic that can activate the immune system by presenting an antigen to lymphocytes, thus killing tumor cells. The former vaccine usually contains an antigen alone or with an adjuvant, which cannot be recognized by lymphocytes effectively. With nanocarriers, vaccines could effectively target specific organs and transform them into cells. The nucleic acid vaccine, especially the mRNA vaccine, has become one of the most potent tools against diseases such as covid-19 and cancer because of its long-term effect and safety. Once mRNA enters the cell, it can express specific proteins continuously, thus making immune cells produce antibodies. A nanovaccine formed with ovalbumin mRNA and adjuvants (R848) was loaded in injectable hydrogel to gain the enhanced effect.118 The nanovaccine could generate an OVA 30 days after one injection and target lymph nodes. Results show that generating tumor antigen antibodies in the serum could effectively prevent metastasis formation (Figure 4B). To encapsulate individual tumor mRNA into cationic lipid nanoparticles, the RNA-NPs could activate systemic and intratumoral myeloid cells.119 Positive charge lipid nanoparticles encapsulating untargeted tumor RNA can activate the response to immunotherapy. Codelivery of anti-PD-L1 mAbs and RNA-NPs could increase peripheral/intratumoral PD-1+ CD8+ cells and elicits antitumor activity in “cold” tumor models resistant to ICI monotherapy. Nanovaccine could also work together with implantable materials to gain an enhanced efficacy. A blood clot scaffold loading liposome vaccine and siRNAs was developed to recruit and induce the maturation of DCs and reduce immunosuppressive signals in mature DCs120. By loading PD-L1/TIM-3 siRNA, the scaffold could reduce the expression of immunosuppressive molecules in DCs thus stimulating a strong immune response against tumors. It can also treat different tumors by changing tumor antigens. The system can be optimized by encapsulating components into the same nanoparticle in the future.120

3.4.4. Changing Tumor Microenvironment from Cold to Hot

Besides using nucleic acids to stimulate the immune system against the tumor, utilizing ICI, cytokines, and other immunostimulatory molecules could also heal cancer by the immune system. However, the immunosuppressive tumor microenvironment significantly limits these traditional immunotherapies for their low pH, hypoxia, etc. By transferring a specific gene or interfering with gene expression, the tumor microenvironment could be changed, enhancing the effect of immunotherapy. The nanoparticles named RGD-DMA encapsulating CCL19-encoding plasmid DNA (CCL19 pDNA) and immune checkpoint ligand PD-L1 inhibitor (BMS-1) were developed to overcome the immunosuppressive TME and gain enhanced efficacy.121 CCL-19 could stimulate T cell proliferation, thus increasing IFN-γ secretion in the TME, while BMS-1 could inhibit the expression of PD-L1 more efficiently. Nanoparticles could reshape the TME and inhibit cancer’s abdominal dissemination (Figure 4C). Tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles with thymine functionalization were designed to gain the enhanced gene delivery capacity and adjuvant immune properties by activating the stimulator of interferon genes (STING) pathway.122 TT-LDCP NPs could deliver siRNA against PD-L1 and plasmid DNA, which could encode IL-2 in tumors, activate CD8+ T cells, augment the efficacy of cancer immunotherapy, and suppress tumor progression. A bacterial outer membrane vesicle-based immunotherapeutic agent has been studied for tumor immunotherapy.123 It activates the immune system and disrupts the PD-L1-mediated immunosuppressive tumor microenvironment. PD1-bearing OMVs significantly enhance the antitumor immune response. OMV-PD1 stimulates the tumor infiltration of immune cells and a systemic antitumor immune response. The strong accumulation of the OMV-PD1 at the tumor and the vesicles’ efficient binding to PD-L1 on tumor cells deplete tumor cell PD-L1 and ultimately block the PD1/PD-L1 inhibitory axis. The combination of immune activation and blockage of PD1/PD-L1 leads to a significant reduction in tumor growth in mouse melanoma and colorectal cancer models. The engineered bacterial extracellular vesicle-based system provides an exciting opportunity to further develop tumor immunotherapy strategies (Figure 4D).

In summary, combining immunotherapy with gene therapy can enhance the therapeutic effect of cancer treatment. Oncolytic virus therapy combined with gene therapy has also shown promise in disrupting immunosuppression within tumors and promoting antitumor immune responses. Nucleic acid-based vaccines, such as mRNA vaccines, have become powerful tools against cancer due to their long-term effect and safety. Changing the tumor microenvironment by gene therapy can also enhance the effectiveness of immunotherapy.

4. Conclusion and Future Perspective

Combined gene therapy has many advantages that a single therapeutic cannot achieve, such as preventing tumor metastasis and recurrence, enhanced therapeutic efficiency, etc. By encapsulating drugs into nanocarriers, the delivery system could achieve targeting ability, lysosome escape, and other functions. Understanding the mechanisms of synergistic therapeutic effects is crucial for designing therapeutic schemes and the forms of nanocarriers. However, there are still several barriers to combining gene therapy with nanoplatform. First, the metabolism and toxicity of different nanocarriers must be researched systematically. Although many nanocarriers have been researched, a smaller number of carriers have been approved by the FDA. Before clinical use, it is crucial to thoroughly investigate the interaction between various nanomaterials and organisms as well as determine whether these materials can be degraded in vivo. These factors must be clearly understood to ensure safe and effective use. Second, the efficiency of gene transformations still has much room for improvement. How to synthesize a nanocarrier that could deliver specific nucleic acids into cells with no apparent toxicity is a big challenge. Besides, the transform of gene drugs is critical for evaluation of dosage of administration and the proportion of drugs contained in the delivery system. Third, the long-term effects of combined therapy should be investigated, which should observe if gene drugs have other effects on normal organs and if it is suitable for long-term use. Gene therapy is a highly sought-after treatment option due to its ability to provide a cure with just one dose or treatment, unlike other therapies. However, to ensure optimal therapeutic results, it is crucial to assess the appropriate interval of time for combined therapy prior to clinical use.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (31971318, 22027810, 32101091) and China Postdoctoral Science Foundation (2021M690043).

Author Contributions

CRediT: Jinhui Lin formal analysis (equal), validation (equal), writing-original draft (lead); Xinlian Wang resources (supporting); Dongqi Ni writing-original draft (supporting); Yandong Chen resources (supporting), funding acquisition (supporting); Chunying Chen funding acquisition (lead), writing-review & editing (equal); Ying Liu conceptualization (lead), funding acquisition (equal), writing-review & editing (lead).

The authors declare no competing financial interest.

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