Temperature-sensitive organic nanoparticles with AIE effect were assembled in water from tetraphenylethene-based poly(N-isopropylacrylamide) (TPE-PNIPAM), which was synthesized by ATRP using TPE derivative as initiator. The size and fluorescence of TPE-PNIPAM nanoparticles can be tuned by varying the temperature. These nanoparticles can be internalized readily by HeLa cells and can be used as long-term tracer in live cells to be retained for as long as seven passages.

Phototherapy is effective for triggering the immunogenic cell death (ICD) effect. However, its efficacy is limited by low 1O2 generation and photothermal conversion efficacy due to two irreconcilable obstacles, namely the aggregation‐caused‐quenching (ACQ) effect and photobleaching. In this work, a discretely integrated nanofabrication (DIN) platform (Pt‐ICG/PES) is developed by facile coordination coassembly of cisplatin (Pt), photosensitizer molecules (indocyanine green (ICG)), and polymeric spacer (p(MEO2MA‐co‐OEGMA)‐b‐pSS (PES)). By controlling the ICG/PES feeding ratio, the aggregation of ICG can be easily tailored using PES as an isolator to balance the ACQ effect and photobleaching, thereby maximizing the phototherapy potency of Pt‐ICG/PES. With the optimized ratio of each component, Pt‐ICG/PES integrates the complementarity of photodynamic therapy, photothermal therapy, and chemotherapeutics to magnify the ICD effect, exerting a synergistic antitumor immunity‐promoting effect. Additionally, temperature‐sensitive PES enables photothermally guided drug delivery. In a tumor‐bearing mouse model, Pt‐ICG/PES elicits effective release of danger‐associated molecular patterns, dendritic cell maturation, cytotoxic T lymphocytes activation, cytokine secretion, M2 macrophage repolarization, and distal tumor suppression, confirming the excellent in situ tumor ICD effect as well as robust systematic antitumor immunity. Ultimately, a versatile DIN strategy is developed to optimize the phototherapeutic efficacy for improving antitumor effects and strengthening systemic antitumor immunity.

The combination of photothermal therapy (PTT) with chemotherapy has great potential to maximize the synergistic effect of thermo-induced chemosensitization and improve treatment performance. To achieve high drug-loading capacity as well as precise synchronization between the controllable release of chemotherapeutics and the duration of near-infrared PTT, in this work, a facile one-step method was first developed to fabricate a novel injectable in situ forming photothermal modulated hydrogel drug delivery platform (D-PPy@PNAs), in which a PNIPAM-based temperature-sensitive acidic triblock polymer [poly­(acrylic acid-b-N-isopropylamide-b-acrylic acid (PNA)] was utilized as the stabilizing agent in the polymerization of polypyrrole (PPy). The in situ forming hydrogels showed a sensitive temperature-responsive sol–gel phase-transition behavior, as well as an excellent photothermal property. The strong interaction of ionic bonds together with π–π stacking interactions resulted in high doxorubicin (DOX) loading capacity and controlled/sustained drug release behavior. In addition, D-PPy@PNAs also displayed enhanced cellular uptake and promoted intratumoral penetration of DOX upon NIR laser irradiation. The synergistic photothermal therapy–chemotherapy of D-PPy@PNA hydrogels greatly improved the antitumor efficacy in vivo. Therefore, thermosensitive polypyrrole-based D-PPy@PNA hydrogels may be powerful drug delivery nanoplatforms for precisely synergistic photothermo-chemotherapy of tumors.

Photodynamic therapy (PDT), is a rising star for suppression of in situ and metastatic tumors, yet it is impeded by low ROS production and off-target phototoxicity. Herein, an aggregation degree editing strategy, inspired by gene editing, was accomplished by the coordination of an aggregation degree editor, p(MEO2MA160-co-OEGMA40)-b-pSS30 [POEGS; MEO2MA = 2-(2-methoxyethoxy)­ethyl methacrylate, OEGMA = oligo­(ethylene glycol) methacrylate; pSS = poly­(styrene sulfonate)] and indocyanine green (ICG) to nontoxic Mg2+, forming an ICG discretely loaded nanoaggregate (ICG-DNA). Optimization of the ICG aggregation degree [POEGS/ICG (P/I) = 6.55] was achieved by tuning the P/I ratio, alleviating aggregation-caused-quenching (ACQ) and photobleaching concurrently. The process boosts the PDT efficacy, spurring robust immunogenic cell death (ICD) and systemic antitumor immunity against primary and metastatic immunogenic “cold” 4T1 tumors via intratumoral administration. Moreover, the temperature-sensitive phase-transition property facilitates intratumoral long-term retention of ICG-DNA, reducing undesired phototoxicity to normal tissues; meanwhile, the photothermal-induced tumor oxygenation further leads to an augmented PDT outcome. Thus, this simple strategy improves PDT efficacy, boosting the singlet oxygen quantum yield (Φ Δ)-dependent ICD effect and systemic antitumor responses via local treatment.