Monolayer LDH Nanosheets with Ultrahigh ICG Loading for Phototherapy and Ca²⁺-Induced Mitochondrial Membrane Potential Damage to Co-Enhance Cancer Immunotherapy

Abstract

Tumor recurrence and metastasis are the main causes of cancer mortality; traditional chemotherapeutic drugs have severe toxicity and side effects in cancer treatment. To overcome these issues, here, we present a pH-responsive, self-destructive intelligent nanoplatform for magnetic resonance/fluorescence dual-mode image-guided mitochondrial membrane potential damage (MMPD)/photodynamic (PDT)/photothermal (PTT)/immunotherapy for breast cancer treatment with external near infrared (NIR) light irradiation. To do so, we construct multifunctional monolayer-layered double hydroxide (LDH) nanosheets (MICaP), co-loading indocyanine green (ICG) with ultrahigh loading content realized via electrostatic interactions, and calcium phosphate (Ca3(PO4)2) coating via biomineralization. Such a combined therapy design is featured by the outstanding biocompatibility and provokes immunogenic cell death (ICD) of tumors toward cancer immunotherapy. The active transport of excess Ca2+ released from pH-sensitive Ca3(PO4)2 can induce MMPD of tumor cells to minimize oxygen consumption in the tumor microenvironment (TME). The presence of ICG not only generates singlet oxygen (1O2) to induce apoptosis by photodynamic therapy (PDT) but also initiates tumor cell necrosis by photothermal therapy (PTT) under near-infrared (NIR) light radiation. Eventually, the immune response generated by MMPD/PDT/PTT greatly promotes a cytotoxic T lymphocyte (CTL) response that can limit tumor growth and metastasis. Both in vitro and in vivo studies indeed illustrate outstanding antitumor efficiency and outcomes. We anticipate that such precisely designed nanoformulations can contribute in a useful and advantageous way that is conducive to explore novel nanomedicines with notable values in antitumor therapy.

Stimuli‐responsive nanodelivery systems for amplifying immunogenic cell death in cancer immunotherapy

“…92 A pH-responsive, self-destructive intelligent nanoplatform for Ca 2+ -induced mitochondrial membrane potential damage/PDT/ PTT under NIR light irradiation provokes ICD of tumor cells and enhances cancer immunotherapy. 93 Mitochondrial dynamics is involved in the response and activation of immune cells, especially modulation of macrophage polarization. 94 When the mitochondria of TAMs are in a fission status, antigen-specific immune response is facilitated, notably inhibiting tumor growth.…”

“…Mitochondria are double‐membrane organelles, which provide energy for cells and alter cellular morphology via a reverse event of fusion and fission, termed as mitochondrial dynamics 92 . A pH‐responsive, self‐destructive intelligent nanoplatform for Ca 2+ ‐induced mitochondrial membrane potential damage/PDT/PTT under NIR light irradiation provokes ICD of tumor cells and enhances cancer immunotherapy 93 . Mitochondrial dynamics is involved in the response and activation of immune cells, especially modulation of macrophage polarization 94 .…”

PEI-Based Nanoparticles for Tumor Immunotherapy via In Situ Antigen-Capture Triggered by Photothermal Therapy

“…Several cancer vaccines based on neoantigens have been shown to be safe and effective in clinical studies. − Cancer vaccines combined with immune checkpoint inhibitors (ICIs), including programmed death-1 (PD-1) receptors and CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4), bring hope to reversing “cold tumors” that are resistant to conventional immunotherapies. ,, Traditional strategies of treating tumors (such as radiotherapy, chemotherapy, − photothermal therapy, etc.) can cause tumor cells to undergo immunogenic cell death (ICD), leading to in situ production of tumor antigens and damage-associated molecular patterns (DAMPs) such as calreticulin (CRT), − which may induce tumor-specific immune response. − However, most tumor antigens are very low in quantity, structurally diverse, prone to degradation, and only weakly immunogenic, therefore not sufficient to activate the immune system …”

Simultaneous Imaging and Photodynamic‐Enhanced Photothermal Inhibition of Cancer Cells Using a Multifunctional System Combining Indocyanine Green and Polydopamine‐Preloaded Upconversion Luminescent Nanoparticles

“…[16] Among these, indocyanine green (ICG) is recognized as a useful PTT agent. [17][18][19] It is a commercially available NIR dye and is approved by the Food and Drug Administration. The presence of ICG provides additional advantages for the photodynamic therapy (PDT) of cancer cells.…”