Core-shell tecto dendrimer-mediated cooperative chemoimmunotherapy of breast cancer

The host immune system always identifies and eliminates tumor cells through multiple pathways [1,2]. To form effective anticancer immune response, cancer cell-associated antigens are first captured by antigen-presenting cells (APCs) to promote the maturation of APCs. Then, the matured APCs trigger and stimulate effector T cell responses through presenting the tumor antigens [2]. That is, the major histocompatibility complex (MHC) I and MHC II molecules bind to antigenic peptides through the peptide-binding groove and present the antigens on the cell surface for recognition by T cells. Finally, the effector T cells specifically recognize and kill cancer cells. However, complete cure of cancer is rare due to the blocked anticancer immune response by various pathways. Current cancer immunotherapy modes (e.g., immune checkpoint-blockade (ICB) therapy, chimeric antigen receptor T cell therapy, etc.) have shown some positive therapeutic effects in clinical practice [3,4], but in fact cancer immunotherapy is still in its infancy owing to the lack of a positive response to immune checkpoint therapy in the majority of the population, the associated toxicity of CAR-T cells themselves, and the other limitations [5].

In the field of nanomedicine, nanomaterials have been developed to elicit intrinsic and durable immune responses, particularly through the conversion of “cold” tumors to “hot” tumors by altering the tumor microenvironment to generate enduring antitumor immune responses [6,7]. For instance, nanoparticles (NPs) are adopted to induce immunogenic cell death (ICD) in cancer cells through chemotherapy [8,9], photothermal therapy [[10], [11], [12]], or photodynamic therapy [[13], [14], [15]], and so on [2,16,17]. Due to the design characteristics of NPs, the combination of conventional therapy and ICD effect can enhance the antigen presentation of dendritic cells (DCs), trigger the activation of T cells, increase the immune stimulation and destroy the immunosuppressive effect of solid tumors. However, ICD-triggered tumor microenvironment remodeling can only provide suboptimal cancer immunotherapy outcomes and can easily lead to secondary tumor immune escape [17]. In order to achieve efficient antitumor immune response, nanomaterials-enabled cancer cell ICD effect has been combined with ICB, particularly through programmed cell death ligand 1(PD-L1) or CD47 antibody to achieve effective antitumor combination therapy [9,[18], [19], [20]]. However, the implementation of antibodies is quite expensive and usually requires a high dose with limited efficiency [21,22].

Despite the presence of a large number of neoantigens, it is still difficult to achieve complete tumor cure owing to the failure to obtain a considerable and durable antitumor immunity [23,24]. This should be attributed to the immune evasion effect of DCs with limited antigen-presenting capacity. Thus, the mere ICD effect cannot effectively induce the required DC maturation and T cell activation in lymph nodes [17]. It is of paramount significance to develop effective nanomedicine formulations to enhance both the immunogenicity of cancer cells and the antigen-presenting ability of APCs for cytotoxic T lymphatics (CTLs) infiltration at tumor site for effective cancer chemoimmunotherapy.

Recently, it has been suggested that antitumor immunity can be controlled by mRNA N6-methyadenosine (m6A) methylation regulated by the m6A-binding protein YTHDF1 (a vital reader protein for RNA m6A methylation) in DCs [24]. In general, YTHDF1 can recognize transcripts encoding lysosomal proteases (TELPs) marked by m6A, leading to increased translation of TELPs. The YTHDF1 protein in DCs is one of the potential therapeutic targets to exert tumor immunotherapy. The downregulation of YTHDF1 protein in DCs renders them with enhanced cross-presentation of tumor antigens and the subsequent cross-priming of CD8+ T cells [24,25]. Our previous work has shown that zwitterionic dendrimer-entrapped gold NPs can deliver YTHDF1 siRNA to DCs to silence the expression of YTHDF1 protein, thus boosting efficient tumor immunotherapy through the combination of PD-L1 antibody [25].

Currently, core-shell tecto dendrimers (CSTDs) generated by supramolecular recognition have attracted much attention due to their superiority to single-generation dendrimers [26,27]. Studies have displayed that generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers decorated by β-Cyclodextrin (β-CD) as cores can be assembled with generation 3 (G3) PAMAM dendrimers modified by adamantane (Ad) as shells through supramolecular recognition to form G5-CD/Ad-G3 (G5/G3) CSTDs [28]. The prepared G5/G3 CSTDs exhibited higher gene transfection [26] and drug loading efficiency [27,29], and stronger r1 relaxivity after gadolinium (III) (Gd(III)) chelation and enhanced permeability and retention effect (EPR) effect [30] than the single G5 dendrimer counterpart materials. At present, the formed G5/G3 CSTDs have been successfully utilized for combination chemotherapy and gene therapy of breast cancer cells in vitro via co-delivery of anticancer drug doxorubicin (DOX) and microRNA 21 inhibitor [29]. After Gd (III) chelation, the CSTD-Gd nanocomplexes can be employed for enhanced magnetic resonance (MR) imaging of a breast cancer model in vivo through amplified tumor EPR effect [30]. In addition, G3-Ad molecule as an independent module can be modified with pyridine, dermorphin and RGD peptide, respectively, and then assembled onto G5-CD cores to create multifunctional CSTDs for Cu(II) complexation, thus achieving chemodynamic therapy of orthotopic glioma under MR imaging guidance [31]. However, there is a lack of literature involving CSTD-based nanomedicine formulation for chemoimmunotherapy of tumors by fully taking the advantages of CSTDs in terms of their better gene/drug delivery efficiency and tumor penetration/EPR effect than the single-generation dendrimer counterparts.

Herein, we attempted to construct two CSTD-based nanomodules for programmed treatment of cancer cells and DCs, respectively to exert enhanced chemoimmunotherapy of an orthotopic breast cancer through tumor chemotherapy, chemotherapy-induced ICD effect, and positive modulation of DCs (Fig. 1). On one hand, acetylated G5/G3 CSTDs were first formed to encapsulate DOX to constitute G5.NHAc/G3.NHAc/DOX (for short, G5-G3-D) complexes as a nanomodule to treat cancer cells for ICD generation in vitro and in vivo. On the other hand, G3-Ad modified with mannose (Man) were assembled with G5-CD to create G5/G3-Man CSTDs, which were then embellished with zwitterionic molecules, carboxybetaine acrylamide (CBAA), to form CBAA-G5/G3-Man. The prepared CBAA-G5/G3-Man with antifouling and affinity properties were used to deliver YTHDF1 siRNA to DCs for stimulate the maturation of DC cells in vitro and in vivo. The created nanomedicine formulations were thoroughly characterized, and their therapeutic efficacy was fully evaluated using an orthotopic murine breast tumor model (4T1 cells) after programmed treatment of both affinity of cancer cells and DCs with the respective CSTD-based nanomodules. To the best of our knowledge, our study represents the very first case to develop CSTD-based nanomedicine formulations for programmed treatment of cancer cells and DCs to exert effective tumor chemoimmunotherapy.

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