Cold to Hot: Binary Cooperative Microneedle Array-Amplified Photoimmunotherapy for Eliciting Antitumor Immunity and the Abscopal Effect

Abstract

In this study, an ingenious core–shell structure microneedle (CSMN) array was designed to synergistically boost robust immune response by the intralesional codelivery of photosensitizer and indoleamine 2,3-dioxygenase (IDO) blockade. Photosensitizer indocyanine green was encapsulated into chitosan nanoparticles (ICG-NPs), followed by concentrating on the tip shell of microneedles. 1-Methyl-tryptophan was loaded into the cross-linked poly­(vinyl pyrrolidone) and poly­(vinyl alcohol) gel as the microneedle core. Through the direct deposition of the ICG-NP-loaded tips into the tumor site with uniform spatial distribution, the CSMNs effectively converted the near-infrared laser into heat to ablate primary tumors, generated tumor-associated antigens and damage-associated molecular patterns, and promoted the maturation of dendritic cells and the secretion of immunostimulatory cytokines. The IDO blockade further reversed the IDO-mediated immunosuppression, ultimately arousing an effective systematic immune response. The in vivo results showed that 80% of the melanoma tumor was eradicated, followed by a relapse-free survival in more than 120 days. Of note, this synergistic strategy significantly inhibited lung metastasis and controlled the development of already metastasized tumors. Our work provides a new, generalizable framework for using the microneedle-based photothermal therapy to initiate antitumor immunity and sensitize tumors to IDO blockade.

Microneedles for painless transdermal immunotherapeutic applications

“…IDO is able to catalyze the degradation of tryptophan into kynurenine, which, in turn, gives rise to impairment of CD8 + T cells activation and inhibition of their antitumor ability via increased activity of regulatory T cells (Tregs) [90,91]. To address these limitations of PPT, Chen et al engineered an ingenious core-shell structure MN (CSMNs) array that was able to synergistically boost robust immune response through intralesional co-delivery of a photosensitizer and IDO blocking agent [92]. They loaded 1-methyl-tryptophan (1-MT) into the cross-linked PVP and poly (vinyl alcohol) gel as the MN core and encapsulated photosensitizer indocyanine green into chitosan nanoparticles (ICG-NPs), followed by concentrating on the tip shell of MNs.…”

Recent advances in microneedles-mediated transdermal delivery of protein and peptide drugs

“…Therefore, integrating MNs with immunomodulatory antibody is promising for fighting against malignant tumors. In particular, nanoparticles-encapsulated MNs have been designed to enable controlled release of immune checkpoint inhibitors, including aPD-1/aPD-L1 189,190 , aCTLA-4 191,194 , and 1-methyl-D,L-tryptophan 192 , 194 . Wang et al.…”

“…Immune checkpoint blockade therapy based on MNs can be combined with other cancer therapies. Besides, the activation of the skin immune system can enhance anti-cancer immunity both locally and systemically 190 , 194 . Chen et al.…”

Hitchhiking on Controlled-Release Drug Delivery Systems: Opportunities and Challenges for Cancer Vaccines

“…Although ISV and its combinatorial therapies are gaining rising attention among researchers, the magnitude and durability of antitumor immune responses induced by ISV could be unfortunately impeded by the immunosuppressive tumor microenvironment ( van der Burg et al, 2016 ). One appealing strategy is to introduce CAR-T, ICIs or other immunosuppressive signal inhibitors in the combinatorial therapies to improve the outcomes ( Wang et al, 2018 ; Chen et al, 2019a ; Song et al, 2019 ; Chen et al, 2020a ). Moreover, approaches that loosen the desmoplastic stroma or target the tumor vasculature would help to augment the antitumor immunity of ISV by facilitating immune infiltration ( Galluzzi et al, 2018 ).…”

“…Antigen-specific humoral and cellular immunity protection were found to be elicited after administration, leading to a significant antitumor activity in the EG7-OVA tumor-xenograft mice. Since MNs are usually applied topically on the surface of the skin, they are very suitable to be combined with phototherapy ( Ye et al, 2017 ; Chen et al, 2020a ). One example of such combination therapies was based on the tumor lysates, melanin and GM-CSF were loaded into hyaluronic acid-based MNs that allowed sustained release of the lysates ( Ye et al, 2017 ).…”