*4.1. Passive Immune Nanomedicine*

Passive immune nanomedicine involves NPs conjugated with growth factors, cytokines and nucleic acids, which intervene by stimulating the maturation, activation or inhibition of some cells of the innate immune response, as well as enhancing the antigenic presentation, with the final objective of activating the adaptive immune response.

Synthetic and natural NPs have physical and chemical ideal properties that make them optimal drug carrier platforms for targeted delivery, such as allowing their pharmacokinetic and pharmacodynamic properties to be modified without altering their anti-tumour effect. The surface of these NPs is directly modified with chemical motifs for selective and/or oriented coupling/immobilization of different biomolecular targets. Commonly, among chemical moieties, a plethora of biomolecules could be bound to the surfaces such as: antibodies, peptides or recombinant proteins, DNA probes, in order to facilitate the selective accumulation of drugs within the tumour tissues when they are released from the internal nucleus of the NP, where they are encapsulated [193].

**Figure 12.** Classification of nanomedicines according to the function caused/promoted on the immune cells [193].

Here, a few of the most representative NPs involved in the multiple functions mentioned above will be further discussed in order to reflect the advantages in oncotherapy.

Lipid-based and polymer-based NPs allow effective delivery of antigens or viral peptides to APC to stimulate memory T-cell responses to tumours. Self-assembled NPs increase the production of inflammatory cytokines such as IL-2 and IFN-γ in activated leukocytes, generating powerful immune responses to low immunogenic tumours.

In this area, another described application of NPs is to produce direct delivery of cytokines, cell growth factors or stimulant cocktails to activate specific or particular functions of immune cells. NPs capable of delivering nucleic acids such as siRNAs or Cas9 mRNAs have also begun to be used to intervene in transcriptional modifications or repair genes associated with disease [193].

One example is the reprogramming of circulating T cells to the anti-tumour phenotype by inserting chimeric antigen receptor (CAR) genes for leukemia into the nucleus using containing synthetic DNA coupled to NPs [194], which offers some advantages over current CAR-T cell therapy, such as replacing the ex vivo expansion of T cells isolated from the patient. In the case of RNA, sequences encoding viral neo-antigens or mutants are used [193], and it is encapsulated in lipid NPs that protect it from degradation by extracellular ribonuclease, ensuring its internalization into APCs so that they express in vivo engineered antigenic peptides [195]. The use of the latter type of NPs has been shown to induce anti-tumour effects and memory T cells, through the activation of INF-α, and induced strong anti-tumour anti-specific responses in three melanoma patients [51].

NPs present another potential advantage, namely targeted immunization, since they are mostly captured (by different mechanisms such as phagocytosis, pinocytosis, and endocytosis) by innate immune cells such as macrophages, monocytes and dendritic cells. The surface of these NPs is a binding substrate for serum proteins such as albumin, apolipoproteins and complement system, forming a biological corona that interacts with different receptors that are expressed in membrane of professional phagocytic cells (i.e., macrophages, DCs, etc.). Although this non-specific absorption by phagocytic cells may be a disadvantage in the case of conventional nanomedicine because it reduces the accessibility and availability of encapsulated drugs in tumour tissues; however in the case of immune nanomedicine it may be an advantage, since these NPs can thus reach lymphoid organs such as the spleen and produce their immunomodulatory effect there.

These properties make NPs outstanding candidates for the administration of tumour vaccines and/or vaccine adjuvants, as they improve their potential while reducing side effects by preventing the systemic distribution of these adjuvants and prolonging their role in lymph node drainage [193].

The intervention of NPs in the different processes of innate immunity can improve the efficacy of passive immunotherapy, and it is therefore necessary to develop new strategies to exploit the full potential of nanomaterials combined with different immunotherapeutics. Passive nanomedicine is an approach that offers many possibilities for improving cancer treatment, which should be further investigated with the aim of transferring its benefits to the clinic.
