Triple-negative breast most cancers (TNBC) is an aggressive subtype of breast most cancers characterised by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal development issue receptor 2 (HER2) expression[1]. This molecular profile makes it difficult for conventional therapies like chemotherapy to perform successfully. Photothermal remedy (PTT) has emerged as a promising strategy for TNBC remedy on account of its capacity to selectively ablate tumors utilizing near-infrared (NIR) laser irradiation inside the organic transparency window[2], [3]. Researchers have proposed that combining PTT with different therapeutic modalities, comparable to chemotherapy, can partially overcome the constraints of NIR lasers and scale back residual tumor cells [4], [5]. Moreover, sequential irradiation with twin lasers has additionally emerged as a complete technique to mitigate tumor recurrence and metastasis[6]. Nevertheless, the penetration of photothermal conversion brokers (PTCAs) in strong tumors stays a major impediment. This limitation usually impairs PTT therapeutic efficacy, primarily on account of incomplete tumor ablation, particularly in deep or poorly accessible areas. Fortuitously, past its direct tumor-killing results, PTT can induce immunogenic cell loss of life (ICD), and launch damage-associated molecular patterns (DAMPs) like calreticulin (CRT), adenosine triphosphate (ATP), and excessive mobility group protein 1 (HMGB1). These DAMPs stimulate dendritic cell (DC) maturation and T cell activation, triggering a systemic anti-tumor immune response, which is advantageous for combating residual tumor cells[7], [8]. This twin functionality positions PTT as a possible cornerstone for TNBC immunotherapy.
Nevertheless, the dense ECM in TNBC, composed of fibrous proteins, glycosaminoglycans, and proteoglycans, considerably impedes the supply of PTCAs and the infiltration of immune cells, comparable to CD8+ T cells, into the tumor[9], [10]. Methods that modulate the ECM are crucial to deal with this. Zinc ions (Zn2+) have been proven to upregulate metalloproteinases (MMPs), significantly MMP-2 to degrade ECM parts[11], [12]. As an angiotensin inhibitor, losartan concurrently suppresses cancer-associated fibroblast (CAF) exercise and reduces collagen synthesis by TGF-β signaling inhibition[13], [14]. Combining Zn2+ and losartan affords a synergistic strategy to “upregulate and downregulate” MMP-2 and CAFs respectively for ECM degradation. The ECM density discount enhances the enrichment of PTCAs within the deep tumor. Concurrently, it promotes the infiltration of CD8+ T cells, thereby bettering the effectivity of PTT and its immune impact. One other problem is the technology of warmth stress-related ROS throughout PTT, which is induced by the temperature enhance[15], [16]. Electron leakage from the mitochondrial electron transport chain contributes considerably to intracellular ROS technology. Warmth stress brought on by PTT results in mitochondrial membrane potential depolarization and enhanced electron leakage, leading to ROS elevation[17], [18]. The elevated ROS immediately damages T cell exercise and oxidizes HMGB1, resulting in a discount within the variety of T cells infiltrating the tumor and weakening the anti-tumor immune response[19], [20], [21]. Due to this fact, though the immune response activated by PTT serves as a potent software towards tumor recurrence and metastasis[22], [23], typical photothermal immunotherapy usually neglect the weakening of anti-tumor immunity brought on by elevated ROS. To counteract this, integrating ROS-scavenging capabilities into PTCAs represents a promising technique[24]. As an illustration, PLD (polymerized 3,4-dihydroxyphenylalanine (L-dopa)) is a melanin-like materials, that not solely reveals glorious photothermal conversion properties but additionally comprises catechol teams that successfully scavenge ROS[25], [26]. This twin performance might assist transform the tumor immune microenvironment and improve the anti-tumor immune response post-PTT.
Given the multifaceted challenges in TNBC remedy, there’s a compelling must combine ECM-degradation brokers, PTCAs, and ROS scavengers right into a unified therapeutic platform. Such an built-in strategy would deal with the limitations posed by the dense ECM, improve the efficacy of PTT, and mitigate ROS-induced immunosuppression. Layered double hydroxide nanosheets, that are barely alkaline nanomaterials wealthy in metallic ions [27], [28] and thus very best for the storage and supply of a number of therapeutic brokers comparable to Zn2+, losartan, and PLD, provide a promising resolution for this function. Their sensitivity to the acidic tumor microenvironment and biodegradable properties allow managed and responsive drug launch, making certain exact modulation of the tumor microenvironment.
On this work, the nanohybrid LDH-PLD@Lst was developed for the twin regulation of ECM degradation and ROS scavenging in strong tumors, enhancing photothermal immunotherapy efficacy (Scheme 1). First, Zn2+ loaded MgAl-layered double hydroxide (LDH) was synthesized, adopted by the loading of small-sized PLD by way of coordination to kind PLD-LDH. Subsequently, by the interplay between PLD and the π-conjugated construction of losartan, the nanohybrid LDH-PLD@Lst was obtained. Upon getting into the acidic tumor microenvironment, the protonation of the phenolic hydroxyl teams in PLD and the disruption of π–π stacking between losartan and PLD result in the gradual launch of Zn2+ and losartan from LDH-PLD@Lst. The launched Zn2+ considerably upregulates MMP-2 exercise, resulting in the degradation of dense collagen within the ECM. Concurrently, losartan inhibits CAFs and reduces collagen secretion, additional dismantling the ECM barrier. Moreover, LDH-PLD@Lst releases PLD with catechol teams within the tumor microenvironment, which scavenges ROS and alleviates immunosuppression. This twin regulating technique of ECM degradation and ROS scavenging enhances the penetration of PTCAs and promotes immune response, thereby bettering photothermal immunotherapy. Particularly, LDH-PLD@Lst was synthesized by hydrothermal synthesis, coordination bonding, and π-π stacking, and its potential for responsive launch of Zn2+, losartan, and PLD was investigated in vitro. Collagen degradation and mobile uptake in tumor spheroids had been analyzed to elucidate the penetration-enhancing mechanism. Antitumor efficacy of LDH-PLD@Lst was evaluated each in vitro and in vivo. Additional research demonstrated the results of LDH-PLD@Lst on DAMPs secretion, ROS scavenging, and infiltration of surviving immune cells. By analyzing the tumor suppression outcomes and the efficient modulation of MMP-2, CAFs, and ROS-scavenging for T cells infiltrating, the efficacy of this ECM degrading and ROS-scavenging photothermal immunotherapy technique was validated.
