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Combinational immunotherapy of dendritic cell (DC) vaccines and anti‐programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor‐specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co‐delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co‐deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre‐suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co‐delivery of ovalbumin (OVA)‐pulsed DCs (OVA‐DCs) and aPD1 via cryoMNs induced higher antigen‐specific cellular immune responses compared with the mono‐delivery of OVA‐DCs or aPD1. Finally, administration with cryoMNs co‐encapsulated with OVA‐DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti‐tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA‐DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co‐delivery system of therapeutic cells and biomacromolecules for combinational therapies. [ABSTRACT FROM AUTHOR]

The development of an optimal treatment modality to improve the therapeutic outcome of breast cancer patients is still difficult. Poor antigen presentation to T cells is a major challenge in cancer immunotherapy. In this study, a synergistic immunotherapy strategy for breast cancer incorporating immune cell infiltration, immunogenic cell death (ICD), and dendritic cell (DC) maturation through a reactive oxygen species (ROS)‐responsive dual‐targeted smart nanosystem (anti‐PD‐L1‐TKNP) for the simultaneous release of DOX, R848, and MIP‐3α in the tumor microenvironment is reported. Following local injection, anti‐PD‐L1‐DOX‐R848‐MIP‐3α/thioketal nanoparticle (TKNP) converts tumor cells to a vaccine owing to the combinatorial effect of DOX‐induced ICD, R848‐mediated immunostimulatory properties, and MIP‐3α‐induced immune cell recruitment in the tumor microenvironment. Intratumoral injection of anti‐PD‐L1‐DOX‐R848‐MIP‐3α/TKNP caused significant regression of breast cancer. Mechanistic studies reveal that anti‐PD‐L1‐DOX‐R848‐MIP‐3α/TKNP specifically targets tumor tissue, resulting in maximum exposure of calreticulin (CRT) and HMGB1 in tumors, and significantly enhances intratumoral infiltration of CD4+ and CD8+ T cells in tumors. Therefore, a combined strategy using dual‐targeted ROS‐responsive TKNP highlights the significant application of nanoparticles in modulating the tumor microenvironment and could be a clinical treatment strategy for effective breast cancer management. [ABSTRACT FROM AUTHOR]

Tumor cells can respond to therapeutic agents by morphologic alternations including formation of tunneling nanotubes. Using tomographic microscope, which can detect the internal structure of cells, we found that mitochondria within breast tumor cells migrate to an adjacent tumor cell through a tunneling nanotube. To investigate the relationship between mitochondria and tunneling nanotubes, mitochondria were passed through a microfluidic device that mimick tunneling nanotubes. Mitochondria, through the microfluidic device, released endonuclease G (Endo G) into adjacent tumor cells, which we referred to herein as unsealed mitochondria. Although unsealed mitochondria did not induce cell death by themselves, they induced apoptosis of tumor cells in response to caspase‐3. Importantly, Endo G‐depleted mitochondria were ineffective as lethal agents. Moreover, unsealed mitochondria had synergistic apoptotic effects with doxorubicin in further increasing tumor cell death. Thus, we show that the mitochondria of microfluidics can provide novel strategies toward tumor cell death. [ABSTRACT FROM AUTHOR]

Regulation of the apoptotic pathway plays a critical role in inducing tumor cell death and circumventing drug resistance. Survivin protein is the strongest inhibitor of apoptosis found so far. It is highly expressed in several cancers and is a promising target for cancer therapy. However, clinical applications are limited by incomplete inhibition of survivin expression. Here, we present a novel strategy that extended the release of YM155 (an effective survivin inhibitor that works by inhibiting the activity of survivin promoter) and TATm‐survivin (T34A) (TmSm) protein (survivin protein mutant with penetrating peptide, a potential anticancer protein therapeutic) via tumor matrix microenvironment‐mediated ferritin heavy chain nanocages (FTH1 NCs), enabling significant inhibition of survivin activity at both transcript and protein levels. FTS (FTH1‐matrix metalloproteinase‐2‐TmSm)/YM155 NC synthesis was easily scaled up, and these NCs could sequentially release TmSm protein through matrix metalloproteinase‐2 and promote YM155 to enter the nucleus via transferrin receptor 1 (TfR1) binding, which increased the cytotoxicity and apoptosis of Capan‐2 and A549 cells compared to that with individual drugs. Moreover, FTS/YM155 NCs enhanced drug accumulation at tumor sites and had a higher tumor inhibition rate (88.86%) than the compounds alone in A549 tumor‐bearing mice. In addition, FTS/YM155 NCs exerted significant survivin downregulation (4.43‐fold) and caspase‐3 upregulation (4.31‐fold) and showed better therapeutic outcomes without inducing organ injury, which highlights their promising future clinical application in precision therapy. This tumor microenvironment‐responsive platform could be harnessed to develop an effective therapy via multilevel inhibition of cancer targets. [ABSTRACT FROM AUTHOR]