Self-Delivery Ternary Bioregulators for Photodynamic Amplified Immunotherapy by Tumor Microenvironment Reprogramming

Abstract

Abnormal metabolism of cancer cells results in complex tumor microenvironments (TME), which play a dominant role in tumor metastasis. Herein, self-delivery ternary bioregulators (designated as TerBio) are constructed for photodynamic amplified immunotherapy against colorectal cancer by TME reprogramming. Specifically, carrier-free TerBio are prepared by the self-assembly of chlorine e6, SB505124 (SB), and lonidamine (Lon), which exhibit improved tumor accumulation, tumor penetration, and cellular uptake behaviors. Interestingly, TerBio-mediated photodynamic therapy (PDT) could not only inhibit the primary tumor growth but also induce immunogenic cell death of tumors to activate the cascade immune response. Furthermore, TerBio are capable of TME reprograming by SB-triggered transforming growth factor (TGF)-β blockage and Lon-induced lactic acid efflux inhibition. As a consequence, TerBio significantly suppresses distant and metastatic tumor growth by PDT-amplified immunotherapy. This study might advance the development of self-delivery nanomedicine against malignant tumor growth and metastasis.

Combined Chemo–Immuno–Photothermal Therapy for Effective Cancer Treatment via an All-in-One and One-for-All Nanoplatform

“…The percentage of CD3 + CD8 + T cell for the DTX-loaded Zein NPs group was 29.0%, while that for the DTX-loaded Zein/CSP NPs group increased significantly to 36.5%, indicating that CSP was beneficial to the infiltration of cytotoxic T lymphocytes into tumor tissue. Most strikingly, the distant tumors of mice treated by DTX-loaded Zein/CSP-GTP/Fe III NPs + laser showed the highest percentage of CD3 + CD8 + T cells (47.0%, Figure b) as well as the highest CD3 + CD8 + to CD3 + CD4 + T cell ratio (2.06, Figure d), which implied that the combination therapy could facilitate the intratumoral infiltration of T lymphocytes . TNF-α was a natural immune serum mediator that can produce tumor hemorrhagic necrosis, and IL-6 was a key regulator of tumor accumulation and activation as well as a factor, motivating tumor cell survival, proliferation, metastasis and invasiveness .…”

“…Most strikingly, the distant tumors of mice treated by DTX-loaded Zein/CSP-GTP/Fe III NPs + laser showed the highest percentage of CD3 + CD8 + T cells (47.0%, Figure 9b) as well as the highest CD3 + CD8 + to CD3 + CD4 + T cell ratio (2.06, Figure 9d), which implied that the combination therapy could facilitate the intratumoral infiltration of T lymphocytes. 58 TNF-α was a natural immune serum mediator that can produce tumor hemorrhagic necrosis, 59 and IL-6 was a key regulator of tumor accumulation and activation as well as a factor, motivating tumor cell survival, proliferation, metastasis and invasiveness. 60 Additionally, the levels of TNFα in the serum was significantly increased after the DTXloaded Zein/CSP-GTP/Fe III NPs + laser treatment, and the IL-6 level was also elevated but found no significant difference compared to other groups (Figure 9e,f).…”

In Situ Transformable Supramolecular Nanomedicine Targeted Activating Hippo Pathway for Triple-Negative Breast Cancer Growth and Metastasis Inhibition

“…Consequently, the combined administration of two or more drugs and combined therapy with other treatment methods have become widely used strategies for potentiating pathway-targeted therapy, which can produce much stronger antitumor effects through multitarget and mutitherapy synergism. In the past decades, self-delivered supramolecular nanomedicine has aroused extensive research interest in combined administration and combined therapy, benefiting from the advantages of customized nanostructures, high drug loading efficiency, and excellent biocompatibility. − Among these nanomedicines, the shape-switchable types that undergo a morphological transformation from nanospheres to nanofibers under an external/internal stimulus have gained increasing attention, because they can meet the dual requirements of strong penetration and long retention. − To date, supramolecular nanomedicines that can accurately activate the Hippo pathway for cancer therapy have rarely been explored, warranting much increased effort in this area.…”

Photodynamic Therapy Initiated Ferrotherapy of Self-Delivery Nanomedicine to Amplify Lipid Peroxidation via GPX4 Inactivation

“…However, the poor bioavailability and the randomized biodistribution of drugs will reduce the antitumor effect but increase the potential systemic adverse effect. , In the past decade, diverse drug delivery systems (DDSs) have been developed to regulate biodistributions and improve pharmacological behaviors of drugs. Although great successes have been achieved for targeting delivery, controlled release, and synergistic therapy, clinical translation of nanomedicine is still confronting great challenges in consideration of the metabolism, accumulation, and excretion of drug carriers. , Most recently, self-delivery nanomedicine was proposed for drug delivery without any drug excipients, which remarkably enhanced the physicochemical and pharmacokinetic behaviors with extremely high drug loading capacity. − Nevertheless, the structurally distinct drug pairs could not only determine their synergistic pharmacological effects but also affect their intermolecular non-covalent interactions and self-assembly behaviors. Consequently, the hard-won screen of matched drug pairs had restricted the construction of self-delivery nanomedicine.…”