Commentary Open Access
Volume 1 | Issue 3 | DOI: https://doi.org/10.33696/Nanotechnol.1.011

Cancer Nanomedicine: Strategies to Enhance Tumor Delivery and Immunotherapy

  • 1Institute of Pediatrics, Children’s Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
+ Affiliations - Affiliations

*Corresponding Author

Min Luo, luo_min@fudan.edu.cn

Received Date: September 10, 2020

Accepted Date: October 12, 2020


Nanomaterials with unique size and integrated features allow novel mechanisms for cancer therapy, so nanomedicine offers more possibilities for effective and safe cancer treatment. However, inefficient tumor delivery remains a major challenge in the clinic. In this commentary, we first discuss new designs of nanomedicine to increase tumor accumulation by active targeting strategies. Nanomedicine can be used to improve active targeting via ligand-receptor binding, cell penetration, or specific cell membrane coating, leading to improved therapeutic efficacy and reduced systemic toxicity. In addition, immune cells aredemonstrated as an important component in tumors, and play a critical role in tumor progression and metastasis, here we address tumor-targeting nanomedicine provide unique approaches to remodel the immunosuppressive tumor microenvironment and promote antitumor immune responses.


Cancer nanomedicine was originally developed for more efficient delivery of chemotherapeutic agents into tumor, and has been extensively employed as a therapeutic for cancer treatment owing to its unique features in drug delivery, diagnosis and imaging, as well as the therapeutic nature of some nanomaterials themselves [1,2]. The enhanced permeability and retention (EPR) effect has been considered as the major discipline for development of cancer nanomedicine [3]. By this way, nanomedicines can passively accumulate in tumor due to the large interendothelial gaps and the absence of lymphatic drainage [4,5]. However, the translation of nanomedicine has been limited due to the low clinical effectiveness of EPR effect. According to a retrospective analysis of published studies during 2005-2015, it was founded that only 0.7% of nanoparticle was delivered to solid tumor following systemic administration [6]. Recently, Sindhwani et al. found that the gaps of leaky vessels are not responsible for the penetration into tumor over several different types of tumors [7], as tumor vasculature is mostly continuous, and gaps occur at a very low frequency. It is crucial to explore new strategies to bypass the bottlenecks of traditional nanomedicine delivery.

Besides passive accumulation by EPR effect, nanomaterials can integrate novel mechanisms for active tumor-targeted delivery. Taking advantage of molecular markers overexpressing on tumor tissues compared to normal cells, incorporating specific ligands or antibodies should be considered to promote nanoparticle accumulation in solid tumors. Nanomedicine with penetration-assisted peptides or transformable properties, such as reversible charge, have been explored to increase internalization of drugs through active transport [8].

Immunotherapy could evoke host immunity to kill cancer cells, showing considerable and long-lasting clinical benefit in several tumor types. However, failure of effector T cells to infiltrate into tumors and immunosuppressive environment in tumors limit antitumor immune responses [9]. Nanomedicine aiming at enhancing immunotherapy could act by mechanisms distinct from chemotherapy. Some immune cells, especially myeloid cells, are native targets for nanomedicine. A thorough understanding of the nano-bio interaction will enable the optimal design of nano-immunotherapies targeting immunosuppressive tumor microenvironment and lymphoid tissues, subsequently triggering the release of tumor antigens and intracellular danger signals, which can boost systemic antitumor immune responses.

In this commentary, we discuss mainly the development of nanomedicine that increase tumor accumulation by active targeting strategies, and further reverse tumor immune environment to promote cancer immunotherapy.

Active Delivery of Nanomedicine into Tumor

With deeper understanding of in vivo nano-cellular interactions, we could switch our delivery strategies to enhance active transport drugs into target cells.

Protein interaction can be integrated in the cellnanoparticle interaction. Taking advantage of molecular markers overexpressing on tumor tissues compared to normal cells, ligand-conjugated nanoparticles could enhance the uptake and release of the therapeutic cargo, such as small-molecule drugs and nucleic acids at the tumor site while reduce side effects relative to conventional therapeutics. It has been shown in cancer therapy that the presence of targeting ligands enhances the cellular uptake of nanoparticles through receptor mediated endocytosis [10,11]. Meanwhile monoclonal antibodies (some approved by the FDA as therapeutic antibodies [12-14]) have been widely used as conjugated molecules and showed efficiency [14-16]. For example, paclitaxel-loaded nanoparticle/Herceptin(Trastuzumab, a humanized anti- HER2 monoclonal antibody) complexes had 22.4% higher cytotoxicity in HER2-overexpressing breast cancer cells compared to paclitaxel-loaded nanoparticles and displayed a dependency on their HER2 expression levels[15].

Tumor-penetrating peptides have been widely used to promote tumor accumulation of nanoparticles as a tumortargeting strategy [17-20]. iRGD has been identified as a tumor-penetrating peptide using peptide library displayed on T7 phage [21]. They showed that iRGD targeted to tumors through a three-step process: 1) the RGD motif mediated binding to αv integrins on tumor endothelium; 2) a proteolytic cleavage exposing a binding motif for neuropilin-1; 3) penetration into cells and tissue. iRGD have been utilized to increase tumor penetration of nanoparticles in experimental tumors in vivo, and in human tumors ex vivo [18,22,23]. In a separate example, Kazuki et al. coated Nab-paclitaxel with iRGD. When injected intravenously, the iRGD-abraxane accumulated in the tumor 11-fold more than nontargeted abraxane in BT474 xenograft models, and significantly inhibited the tumor growth [21].

Cell membrane-coated nanoparticle is a novel platform with prolonged circulation. By coating specific cell membrane directly onto the surface of nanoparticles, the resulting particles could gain the native functionalities of the source cells via associated surface markers [24,25]. It was demonstrated that the membrane-coated nanoparticle could significantly enhance the uptake of cells with corresponding receptors. Krishnamurthy et al. have coated monocyte membrane around PLGA nanoparticles loaded with DOX [26]. The surface marker CD49d, a primary ligand to vascular cell adhesion molecule 1 (VCAM-1), was retained on the membrane-coated nanoparticle. When incubated with mouse skeletal myocyte cells with minimal VCAM-1 and many other cell adhesion molecules, the coated and uncoated particles showed little difference. On the contrary, in metastatic MCF-7 cell lines expressing VCAM-1, membrane-coated nanoparticle showed greater cellular uptake and cytotoxicity when compared to noncoated nanoparticle controls (IC50: 12 μM vs. 4 μM). Besides the utilization of existing markers, some functionalization strategies have been developed to introduce additional ligands onto the surface of nanoparticles. Zhilan et al. reported a CDX peptide-incorporated red blood cell membrane-coated nanoparticle. Owing to the high binding affinity between candoxin-derived CDX peptide and nicotinic acetylcholine receptors (nAChRs) expressed on the surface of brain endothelial cells, the nanoparticles showed promising brain targeting efficiency both in vitro and in vivo [27].

Cationic conjugates are reported to increase caveolaemediated endocytosis and transcytosis, which enables transendothelial and transcellular transport, and a relatively uniform distribution throughout the tumor [28]. Shen et al. designed a charge reversal nanoparticle, with γ-glutamyl transpeptidase-responsive camptothecin– polymer conjugate. The overexpressed γ-glutamyl transpeptidase on the luminal endothelial cells of the tumor blood vessels cleaves the γ-glutamyl moieties of the conjugate to generate positively charged primary amines. The conjugate accumulated in tumor 3.2-fold more than nanoparticles without γ-glutamyl transpeptidase in HepG2 xenograft tumor model and yielded a 99% tumorinhibition rate in large tumor [29].

With many advances in ligand engineering and formulation optimization of nanoparticle, active delivery will become a common therapeutic method in the next generation of cancer nanomedicine. Recent study first discovered that in nanomedicine delivery, active transcytosis contributed more in transporting AuNPs into solid tumors than passive EPR [7], but detailed mechanism is not well understood. The role of different trans-endothelial pathways with respect to extravasation of varying nanoparticle types and surface chemistry needs to be further explored.

Nanomedicine Design to Enhance Cancer Immunotherap

Traditional nanomedicine design focuses on improving chemotherapy to directly destroy rapidly growing tumor cells. With the explosive development of immunotherapy, many researchers find that, a considerable or even major part of cells in tumor is immune cells [30]. In this pathological state, immune cells tend to help tumor cells suppress or escape immune response and promote tumor growth [31]. It has been demonstrated that a large fraction of systemically administered nanomedicine is taken up by non-tumor cells [32], including immune cells within secondary lymphoid tissues or tumor microenvironment. With the unique feature of immune cell targeting, nanomedicine could provide opportunities to promote the tumor microenvironment remodeling and continued cancer cell killing.

Tumor-associated macrophages (TAMs) are significant components of the immunosuppressive tumor microenvironment (ITME), displaying an antiinflammatory M2 polarization to support tumor growth and suppress CD8+ T cell recruitment to TME, thus correlated with poor prognosis [33-36]. One of the key features of macrophages is their plasticity, which enables them to change their phenotype in the tumor microenvironment. Once the immunosuppressive immune cells have been re-programmed, these pro-inflammatory M1 phenotypes could contribute to the antitumor activities [37,38].

Taking advantage of their propensity to phagocytose nanoparticles and microparticles, designing nanomedicine aiming to regulate the immunosuppressive activity of TAM is an attractive approach. Rodell et al. reported engineered cyclodextrin nanoparticles which displayed high TAM affinity while perpetuating a considerable loading efficiency of TLR7 and TLR8 agonist R848. After systemic administration, the formulation could alter TAM phenotype and subsequently improve immune response [39]. Some researchers present functionalized ligand onto nanoparticles to enhance macrophage-targeting capability and remodel their function [40,41]. Kulkarni et al. conjugated signal-regulatory protein-α (SIRPα)- blocking antibodies onto LNPs, while simultaneously loaded a small-molecule inhibitor of macrophage colonystimulating factor 1 receptor (CSF1R). The SIRPα-blocking antibody significantly enhanced binding of nanoparticles and macrophage, and both the functionalized ligand and drug helped to reprogram TAMs to a pro-inflammatory phenotype, leading to tumor regression and survival [42].

Danger signal delivery especially STING agonists is a potential strategy that has been shown to stimulate innate immune response and remodel the tumor microenvironment. One major challenge of this strategy is promoting cytosolic drug delivery. Some advances have been achieved lately [43,44]. Daniel et al. reported polymersomes for cGAMP delivery. The pH-responsive formulation could mediate endosomal escape of cGAMP and increase drug activity by several orders of magnitude compared to free cGAMP. Treatment with this nanomedicine resulted in an 11-fold decrease in the tumour growth rate and significant increase in the survival time relative to free cGAMP [45]. Though some novel materials have been developed for efficient danger signal delivery, one requirement for immunostimulation is that the cells have functional sensor proteins. STING heterogeneity and epigenetic silencing in tumors remains a problem [46]. Protein-based biomimicking nanomedicine as a drug delivery carrier could solve this problem. Yanpu et al. developed recombinant TM-deficient STING protein as cGAMP carrier to induce near-complete self-assembly of STINGΔTM (14 nm) into tetramers (29 nm), which is necessary for the binding and phosphorylation of TBK1 and initiation of downstream pathway. The formulation can trigger STING signaling independent of endogenous STING [47]. When applied as adjuvant, cGAMPSTINGΔTM induced strong humoral and cellular immune responses in vivo and showed great antitumor therapeutic efficacy.

Nanomedicine following in situ injection could be trapped in the tumor’s dense extracellular matrix composed of a collagen-rich hydrogel [48,49]. Immunomodulatory agents delivered in this way could maximize accumulation in the TME, while minimize systemic immunostimulation and cell death. A number of clinical trials are currently evaluating direct intratumoral injection of immunotherapies [50]. Yingzhong et al. intratumorally administered an ionizable lipid to induce robust immunogenic cell death (ICD) and enhance tumor cell transfection. With encapsulated selfreplicating IL-12 RNA, the formulation led to rejection of large established tumors and immune memory [51]. This multifunctional single-agent immunotherapeutic is benefit to clinical translation.

Targeting the innate and adaptive immune systems with nanoparticles provides new pathways for immunotherapy. It is hopeful that nanotechnology-based immunotherapy could be an important complement to current therapies that focus on tumor cells.


Non-efficient delivery to the targeted diseased tissue is the major challenge for nanomedicine translation [52]. Some researchers grafted anti-fouling coatings such as PEG [53] and leukocyte membranes [54] to the nanoparticle surface in order to reduce nanoparticle sequestration by the liver and resident cells, showing enhanced circulation time and improved accumulation in tumors. Interestingly, recent study showed that, via adjustment of the lipid type (permanent cationic and anionic or ionizable cationic) and its molar percentages, lipid nanoparticles (LNPs) could be systematically engineered to deliver mRNA into specific organs [55]. Similar result has shown in RNA-lipoplexes vaccine, where near-neutral and slightly negative particles (optimized charge ratio of 1.3:2) provided an exclusively splenic target [56]. Facing the poor tumor accumulation and challenged EPR effect, the strategies to enhance tumor target in an active mechanism are desired. And further efforts to elucidate the mechanisms underlying active transport are required to facilitate its clinical translation.

Immune cells in tumor have been recognized as a considerable target for precise and effective nanomedicine design. Recent progress about reprogramming of myeloid cells at molecular and genetic lvel provide new opportunities for nanomedicine. In addition, further understanding of nano-bio interaction contribute to bio-inspired platform and proper administration route to enhance immunotherapy. However, there is a growing need to further characterization of the tumor immune microenvironment and its distinct classes and subclasses, which relate to the likelihood of response to immunotherapeutics [57]. And experimental models maximally matching patient tumors and immune compartments are desired.


1. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nature Reviews Cancer. 2017 Jan;17(1):20-37.

2. Ferrari M. Cancer nanotechnology: opportunities and challenges. Nature Reviews Cancer. 2005 Mar;5(3):161-71.

3. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Research. 1986 Dec 1;46(12 Part 1):6387-92.

4. Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proceedings of the National Academy of Sciences. 1998 Apr 14;95(8):4607-12.

5. Golombek SK, May JN, Theek B, Appold L, Drude N, Kiessling F, et al. Tumor targeting via EPR: Strategies to enhance patient responses. Advanced Drug Delivery Reviews. 2018 May 1;130:17-38.

6. Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, Dvorak HF, et al. Analysis of nanoparticle delivery to tumours. Nature Reviews Materials. 2016 Apr 26;1(5):1-2.

7. Sindhwani S, Syed AM, Ngai J, Kingston BR, Maiorino L, Rothschild J, et al. The entry of nanoparticles into solid tumours. Nature Materials. 2020 May;19(5):566-75.

8. Ding J, Chen J, Gao L, Jiang Z, Zhang Y, Li M, et al. Engineered nanomedicines with enhanced tumor penetration. Nano Today. 2019 Dec 1;29:100800.

9. Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nature Reviews Clinical Oncology. 2016 Mar;13(3):143-58.

10. Pirollo KF, Chang EH. Does a targeting ligand influence nanoparticle tumor localization or uptake?. Trends in Biotechnology. 2008 Oct 1;26(10):552-8.

11. Farokhzad OC, Langer R. Impact of nanotechnology on drug delivery. ACS Nano. 2009 Jan 27;3(1):16-20.

12. James JS, Dubs G. FDA approves new kind of lymphoma treatment. Food and Drug Administration. AIDS Treatment News. 1997 Dec 5(284):2-3.

13. Albanell J, Baselga J. Trastuzumab, a humanized anti- HER2 monoclonal antibody, for the treatment of breast cancer. Drugs Today (Barc). 1999 Dec 1;35(12):931-46.

14. Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. New England Journal of Medicine. 2009 Apr 2;360(14):1408- 17.

15. Lee AL, Wang Y, Cheng HY, Pervaiz S, Yang YY. The codelivery of paclitaxel and Herceptin using cationic micellar nanoparticles. Biomaterials. 2009 Feb 1;30(5):919-27.

16. Mi Y, Zhao J, Feng SS. Targeted co-delivery of docetaxel, cisplatin and herceptin by vitamin E TPGScisplatin prodrug nanoparticles for multimodality treatment of cancer. Journal of Controlled Release. 2013 Aug 10;169(3):185-92.

17. Wang CF, Sarparanta MP, Mäkilä EM, Hyvönen ML, Laakkonen PM, Salonen JJ, et al. Multifunctional porous silicon nanoparticles for cancer theranostics. Biomaterials. 2015 Apr 1;48:108-18.

18. Song W, Li M, Tang Z, Li Q, Yang Y, Liu H, et al. Methoxypoly (ethylene glycol)-block-Poly (L-glutamic acid)-loaded cisplatin and a combination with iRGD for the treatment of non-small-cell lung cancers. Macromolecular Bioscience. 2012 Nov;12(11):1514-23.

19. Yan Z, Zhan C, Wen Z, Feng L, Wang F, Liu Y, et al. LyP-1-conjugated doxorubicin-loaded liposomes suppress lymphatic metastasis by inhibiting lymph node metastases and destroying tumor lymphatics. Nanotechnology. 2011 Sep 14;22(41):415103.

20. Hu Q, Gu G, Liu Z, Jiang M, Kang T, Miao D, et al. F3 peptide-functionalized PEG-PLA nanoparticles coadministrated with tLyp-1 peptide for anti-glioma drug delivery. Biomaterials. 2013 Jan 1;34(4):1135-45.

21. Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Girard OM, et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell. 2009 Dec 8;16(6):510-20.

22. Sha H, Zou Z, Xin K, Bian X, Cai X, Lu W, et al. Tumorpenetrating peptide fused EGFR single-domain antibody enhances cancer drug penetration into 3D multicellular spheroids and facilitates effective gastric cancer therapy. Journal of Controlled Release. 2015 Feb 28;200:188-200.

23. Cun X, Chen J, Ruan S, Zhang L, Wan J, He Q, et al. A novel strategy through combining iRGD peptide with tumor-microenvironment-responsive and multistage nanoparticles for deep tumor penetration. ACS Applied Materials & Interfaces. 2015 Dec 16;7(49):27458-66.

24. Fang RH, Kroll AV, Gao W, Zhang L. Cell membrane coating nanotechnology. Advanced Materials. 2018 Jun;30(23):1706759.

25. Hu CM, Fang RH, Luk BT, Chen KN, Carpenter C, Gao W, et al. ‘Marker-of-self’functionalization of nanoscale particles through a top-down cellular membrane coating approach. Nanoscale. 2013;5(7):2664-8.

26. Krishnamurthy S, Gnanasammandhan MK, Xie C, Huang K, Cui MY, Chan JM, et al. Monocyte cell membrane-derived nanoghosts for targeted cancer therapy. Nanoscale. 2016;8(13):6981-5.

27. Chai Z, Hu X, Wei X, Zhan C, Lu L, Jiang K, et al. A facile approach to functionalizing cell membrane-coated nanoparticles with neurotoxin-derived peptide for braintargeted drug delivery. Journal of Controlled Release. 2017 Oct 28;264:102-11.

28. Miura S, Suzuki H, Bae YH. A multilayered cell culture model for transport study in solid tumors: Evaluation of tissue penetration of polyethyleneimine based cationic micelles. Nano Today. 2014 Dec 1;9(6):695-704.

29. Zhou Q, Shao S, Wang J, Xu C, Xiang J, Piao Y, et al. Enzyme-activatable polymer–drug conjugate augments tumour penetration and treatment efficacy. Nature nanotechnology. 2019 Aug;14(8):799-809.

30. O’Donnell JS, Teng MW, Smyth MJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nature Reviews Clinical Oncology. 2019 Mar;16(3):151-67.

31. Pandit S, Dutta D, Nie S. Active transcytosis and new opportunities for cancer nanomedicine. Nature Materials. 2020 May;19(5):478-80.

32. Dai Q, Wilhelm S, Ding D, Syed AM, Sindhwani S, Zhang Y, et al. Quantifying the ligand-coated nanoparticle delivery to cancer cells in solid tumors. ACS Nano. 2018 Jul 17;12(8):8423-35.

33. Petty AJ, Li A, Wang X, Dai R, Heyman B, Hsu D, et al. Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment. The Journal of Clinical Investigation. 2019 Oct 22;129(12).

34. Zhou X, Zhang Z. Foxp3 instability helps ttregs distinguish self and non-self. Frontiers in Immunology. 2019;10:2226.

35. Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. Journal of Hematology & Oncology. 2017 Dec;10(1):1-2.

36. Li Y, Patel SP, Roszik J, Qin Y. Hypoxia-driven immunosuppressive metabolites in the tumor microenvironment: new approaches for combinational immunotherapy. Frontiers in Immunology. 2018 Jul 16;9:1591.

37. Yang L, Wang F, Wang L, Huang L, Wang J, Zhang B, et al. CD163+ tumor-associated macrophage is a prognostic biomarker and is associated with therapeutic effect on malignant pleural effusion of lung cancer patients. Oncotarget. 2015 Apr 30;6(12):10592-603.

38. Zanganeh S, Hutter G, Spitler R, Lenkov O, Mahmoudi M, Shaw A, et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nature Nanotechnology. 2016 Nov;11(11):986-94.

39. Rodell CB, Arlauckas SP, Cuccarese MF, Garris CS, Li R, Ahmed MS, et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nature Biomedical Engineering. 2018 Aug;2(8):578-88.

40. Yuan H, Jiang W, Von Roemeling CA, Qie Y, Liu X, Chen Y, et al. Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy. Nature Nanotechnology. 2017 Aug;12(8):763-9.

41. Conde J, Bao C, Tan Y, Cui D, Edelman ER, Azevedo HS, et al. Dual targeted immunotherapy via in vivo delivery of biohybrid RNAi-peptide nanoparticles to tumor-associated macrophages and cancer cells. Advanced Functional Materials. 2015 Jul;25(27):4183-94.

42. Kulkarni A, Chandrasekar V, Natarajan SK, Ramesh A, Pandey P, Nirgud J, et al. A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer. Nature Biomedical Engineering. 2018 Aug;2(8):589-99.

43. Song W, Shen L, Wang Y, Liu Q, Goodwin TJ, Li J, et al. Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PDL1 trap. Nature Communications. 2018 Jun 8;9(1):1-1.

44. Hewitt SL, Bai A, Bailey D, Ichikawa K, Zielinski J, Karp R, et al. Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs. Science Translational Medicine. 2019 Jan 30;11(477).

45. Shae D, Becker KW, Christov P, Yun DS, Lytton-Jean AK, Sevimli S, et al. Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy. Nature Nanotechnology. 2019 Mar;14(3):269-78.

46. Xia T, Konno H, Barber GN. Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis. Cancer Research. 2016 Nov 15;76(22):6747-59.

47. He Y, Hong C, Yan EZ, Fletcher SJ, Zhu G, Yang M, et al. Self-assembled cGAMP-STINGΔTM signaling complex as a bioinspired platform for cGAMP delivery. Science Advances. 2020 Jun 1;6(24):eaba7589.

48. Kwong B, Liu H, Irvine DJ. Induction of potent antitumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy. Biomaterials. 2011 Aug 1;32(22):5134-47.

49. Irvine DJ, Dane EL. Enhancing cancer immunotherapy with nanomedicine. Nature Reviews Immunology. 2020 Jan 31:1-4.

50. Zhang YN, Poon W, Tavares AJ, McGilvray ID, Chan WC. Nanoparticle–liver interactions: cellular uptake and hepatobiliary elimination. Journal of Controlled Release. 2016 Oct 28;240:332-48.

51. Li Y, Su Z, Zhao W, Zhang X, Momin N, Zhang C, et al. Multifunctional oncolytic nanoparticles deliver selfreplicating IL-12 RNA to eliminate established tumors and prime systemic immunity. Nature Cancer. 2020 Sep;1(9):882-93.

52. Zhang YN, Poon W, Tavares AJ, McGilvray ID, Chan WC. Nanoparticle–liver interactions: cellular uptake and hepatobiliary elimination. Journal of Controlled Release. 2016 Oct 28;240:332-48.

53. Bartneck M, Keul HA, Singh S, Czaja K, Bornemann J, Bockstaller M, et al. Rapid uptake of gold nanorods by primary human blood phagocytes and immunomodulatory effects of surface chemistry. ACS Nano. 2010 Jun 22;4(6):3073-86.

54. Parodi A, Quattrocchi N, Van De Ven AL, Chiappini C, Evangelopoulos M, Martinez JO, et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nature Nanotechnology. 2013 Jan;8(1):61-8.

55. Cheng Q, Wei T, Farbiak L, Johnson LT, Dilliard SA, Siegwart DJ, et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nature Nanotechnology. 2020 Apr;15(4):313-20.

56. Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016 Jun;534(7607):396-401.

57. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nature Medicine. 2018 May;24(5):541-50.

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