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Asian Journal of Pharmaceutical Sciences logoLink to Asian Journal of Pharmaceutical Sciences
. 2026 Mar 27;21(2):101150. doi: 10.1016/j.ajps.2026.101150

A programmable nanoreactor for photothermal immunotherapy via NIR-II triggered enzyme-catalyzed immunogenic tumor microenvironment remodeling

Jiayao Ding a,1, Long Wang b,1, Shengze Lu c, Jingyang Su c,⁎, Jingchao Li a,d,e,⁎
PMCID: PMC13098520  PMID: 42023164

Abstract

The complicated and immunosuppressive tumor microenvironment usually obstruct the efficiencies of various therapeutic schedules including immunotherapy. Here, we report a programmable polymer-based nanoreactor for photothermal-enhanced immunotherapy through second near-infrared (NIR-II) light-triggered enzyme‑catalyzed immunogenic tumor microenvironment remodelling. The nanoreactor system contains a thermal-responsive liposome modified on its surface with xanthine oxidase (XO), and a core co-loaded with a NIR-II-absorbing semiconducting polymer, an oxygen carrier perfluorohexane (PFH) and a hypoxanthine substrate. Under NIR-II laser irradiation, the semiconducting polymer (SP-II) generates a local photothermal effect, directly ablating tumor cells and triggering a phase transition of the liposome shells, enabling precise pulsed release of the loaded contents. The released PFH rapidly alleviates local tumor hypoxia, providing a key substrate for subsequent enzyme cascade reactions. Simultaneously, hypoxanthine is catalyzed by XO to continuously generate superoxide anions and uric acid. In this approach, superoxide anions acting as reactive oxygen species enhance immunogenic cell death and oxidative stress, while uric acid serves as an endogenous danger signal, promoting M2 to M1 repolarization of tumor-associated macrophages, thereby synergistically remodeling the immunosuppressive tumor microenvironment. This strategy potently inhibits laser-irradiated primary tumors, as well as significantly suppresses the progress of distant and metastatic tumors, and prolongs the survival of mouse. Our study provides a new approach for developing programmable anti-tumor nanoreactors with enzyme-catalyzed immunogenic tumor microenvironment remodelling capabilities.

Keywords: Photothermal therapy, Immunotherapy, Uric acid, Nanoreactor, Tumor microenvironment remodeling

Graphical Abstract

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1. Introduction

The complex, heterogeneous tumor microenvironment has been recognized as a core challenge constraining the clinical efficacy of current therapeutic strategies [1,2]. Key bottlenecks such as hypoxia, immunosuppressive microenvironment and limited response to monotherapies are often intertwined, making the developments of novel synergistic treatment paradigms capable of actively remodeling the tumor microenvironment and activating anti‑tumor immunity an urgent need [[3], [4], [5], [6], [7]]. Photothermal therapy (PTT) has garnered significant interest due to its spatial controllability, operational simplicity, and insensitivity to hypoxic conditions [[8], [9], [10], [11], [12]]. However, thermal ablation alone is often considered insufficient for the complete tumor eradication, and the immunogenic cell death (ICD) effect its induced remains limited, making it difficult to effectively reverse the immunosuppressive microenvironment [[13], [14], [15]]. Therefore, simultaneous enhance of treatment‑specific immune responses and synergistic effects through multiple modalities is a key strategy for advancing anti-tumor intervention [[16], [17], [18]].

Uric acid plays a crucial factor in cancer immunotherapy, with its mechanisms of action being highly dependent on concentrations, timing and the microenvironment [19]. When tumor cells undergo extensive death due to treatments or spontaneous necrosis, purine metabolites are released and can form uric acid [20]. Uric acid acts as a key endogenous danger signal activates NLRP3 inflammasome in immune cells [[21], [22], [23], [24], [25]]. This activation promotes the maturation of dendritic cells (DCs) and triggers inflammatory cytokines release, thereby effectively awakening antitumor immune responses [[26], [27], [28]]. At this stage, a positive and adjuvant-like role is played by uric acid in immune process. Thus, its immunostimulatory properties can be utilized to enhance therapeutic efficacy and potentiate immune activation [[29], [30], [31]]. More importantly, uric acid can redirect macrophage functional state from M2 to M1 type, and the transition is considered to have potential significance in enhancing antitumor immunity [8,[32], [33], [34]]. However, the precise controlling of uric acid formation remains a great challenge for its tumor therapy applications.

In recent years, cascade reaction strategies based on nanotechnology have provided innovative approaches for biochemical substance formation. By constructing a single nanoplatform that incorporate multiple functional components, an orderly chain reaction can be triggered at the tumor sites or under specific exogenous stimuli, thereby achieving a synergistic effect [[35], [36], [37]]. Nevertheless, how to combine the physical energy of photothermal therapy with precise biochemical reactions to enable on‑demand reversal of the tumor microenvironment and systemic reprogramming of the immune state alongside local hyperthermia remains a highly challenging frontier research topic [[38], [39], [40]]. In this context, the regulation of programmable reactions by nanoparticles is particularly crucial. Programmable reactions emphasize that, under specific signals or stimuli, the system sequentially activates a series of biological events according to pre‑designed steps, thereby achieving the controllable and precise therapeutic outcomes [41,42]. Due to the skillful integration of stimuli‑responsive elements, nanoplatforms are regarded as ideal tools for realizing programmable reactions [[43], [44], [45]]. The programmed initiation of multi‑stage reactions can be achieved through the sequential release logic enabled by nanoparticles [46,47]. For instance, upon near‑infrared (NIR) light irradiation, localized hyperthermia generated by semiconducting polymer nanoparticles not only directly induced tumor cell ablation but also served as a switch to trigger structural changes in the nanocarriers, thereby enabling precise release of loaded immunomodulators, enzyme substrates or signaling molecules to initiate subsequent biochemical reaction cascades [[48], [49], [50], [51], [52]]. Additionally, the tumor microenvironment, characterized by features such as high reducibility, can be dynamically modulated via multi‑stimuli‑responsive designs of nanoparticles [53,54]. By integrating exogenous stimulus‑response mechanisms (such as light, heat, magnetic field) with these inherent pathological conditions, nanoplatforms enable the programmatic reversal of tumor microenvironmental barriers [[55], [56], [57]].

In this study, a programmable nanoreactor was designed and constructed to integrate PTT and immunotherapy via NIR-II light-triggered enzyme‑catalyzed immunogenic tumor microenvironment remodeling. To realize PTT effect, a NIR-II absorbing semiconducting polymer (SP-II) was designed (Fig. 1A). This nanoreactor system consists of a thermal-responsive liposome with surface modification with xanthine oxidase (XO), while the inside core is co‑loaded with SP-II, oxygen carrier perfluorohexane (PFH) and hypoxanthine (Fig. 1B). With NIR-II laser irradiation, a controllable photothermal effect is generated by SP-II, which can directly ablate tumor cells and trigger a phase transition of the liposome membrane, enabling precise, pulsed release of the encapsulated cargos. PFH, with its exceptional oxygen‑carrying capacity, alleviates the local tumor hypoxia, thereby providing a critical substrate for the subsequent enzymatic cascade. Simultaneously, hypoxanthine is catalyzed by XO through a cascade oxidation reaction, continuously yielding two key bioactive molecules: superoxide anion and uric acid. The superoxide anion, as a potent ROS, further amplifies cellular oxidative stress and enhances the ICD effect. The produced uric acid is an endogenous danger signal to induce the polarization of macrophages from the M2 toward M1. This strategy not only overcomes the oxygen‑dependence of conventional photodynamic therapy but also transcends the limitations of pure PTT‑based physical ablation, achieving an integration of physical ablation, photodynamic-like therapy and immune microenvironment remodeling. As a result, the host’s anti‑tumor immunity is triggered via robust ICD induced by this nanoreactor system and the reversal of immunosuppression, thereby offering a potential approach for suppressing the tumor growths and metastasis (Fig. 1C). Our work contributes a novel design concept and experimental basis for developing programmable nanoplatforms for synergistic anti‑tumor therapy.

Fig. 1.

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Design of programmable nanoreactor (PHX@NPs) for PTT-integrated immunotherapy via NIR-II light-triggered enzyme‑catalyzed immunogenic tumor microenvironment remodeling. (A) Synthetic route of semiconducting polymer (SP-II); (B) Synthesis route of nanoreactor (PHX@NPs); (C) Diagram depicting the working mechanism of nanoreactor -based treatment of tumors.

2. Materials and methods

2.1. Materials

2λ4δ2-Benzo[1,2-c:4,5-c’]bis[1,2,5]thiadiazole,4,8-bis(5-bromo-4-hexyl-2-thienyl)- was purchased from SunaTech Inc (China). 2,6-bis(trimethyltin)-4,8-dioctyloxybenzo[1,2-b:3,4-b]dithiophene was purchased from Bide Pharmatech Ltd (China). Tri-o-tolylphosphine was purchased from Macklin Biochemical Co., Ltd (China). Bovine serum albumin (BSA) was purchased from MP Biomedicals Co., Ltd (China). 1,2-Dipalmitoyl-sn‑glycero-3-phosphorylcholine (DPPC), 1,2-distearoyl-sn‑glycero-3-phosphoethanolamine-N-[succinimidyl (polyethylene glycol)] (DSPE-PEG-NHS), hypoxanthine, and xanthine oxidase (XO) were purchased from MedChemExpress (USA). Perfluorohexane (PFH) was purchased from Adamas (China). PdCl2(PPh3)2, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and 1,3-diphenylisobenzofuran (DPBF) probe were purchased from Sigma-Aldrich (USA). The fluorescence-labeled antibodies were purchased from Biolegend (USA). All test kits were purchased from Beyotime Biotechnology (China).

2.2. Preparation of PHX@NPs

The synthetic procedure for SP-II polymer is as follows: 2λ4δ2-Benzo[1,2-c:4,5-c’]bis[1,2,5]thiadiazole,4,8-bis(5‑bromo-4-hexyl-2-thienyl)- (10.0 mg), 2,6-bis(trimethyltin)-4,8-dioctyloxybenzo[1,2-b:3,4-b]dithiophene (11.0 mg), PdCl2(PPh3)2 (2.5 mg) and tri-o-tolylphosphine (2.0 mg) were dissolved in anhydrous chlorobenzene (5 ml) under nitrogen. The solution was placed in a Schlenk tube and degassed via three freeze-pump-thaw cycles. The polymerization was then performed at 100 °C for 2 h with vigorous stirring. After completion, the mixture was filtered and purified by Soxhlet extraction with methanol.

BSA-SP-II was obtained by dissolving SP-II polymer (0.5 mg) in tetrahydrofuran (THF) and then injecting into a Bovine serum albumin (BSA) solution with ultrasonic conditions for 0.5 h, followed by removal of THF and purification.

A film was constituted by dissolving DSPE-PEG-NHS (20.0 mg), DPPC (20.0 mg), PFH (0.2 ml) and hypoxanthine (0.3 mg) in chloroform (5 ml), with the solvent subsequently removed by evaporation. Film mixed with BSA-SP-II (0.2 ml) and hydrated at approximately 60 °C stir for 1 h. The resulting suspension was homogenized for 60 min prior to being subjected to ultrafiltration for purification. The reaction mixture, following the addition of XO solution in PBS (2.0 mg/ml) was incubated for 48 h at 4 °C under gentle stirring. Final purification was achieved by dialysis to remove free XO, yielding the purified PHX@NPs. The control nanoparticles without hypoxanthine and XO (termed as P@NPs) were also synthesized via the similar protocols.

2.3. Characterization of PHX@NPs

The morphology, hydrodynamic diameters, surface potentials and absorption spectra were characterized by Tecnai G2 transmission electron microscope (TEM), Malvern Zetasizer (NanoZS90) and UV–Vis spectrophotometry, respectively. Following a 2 h incubation of murine erythrocytes with P@NPs, PHX@NPs, negative control (PBS) and positive control (distilled water) at 37 °C, the hemolysis percentage was determined.

2.4. Assessment of photothermal effect and O2·- generation

The aqueous dispersions of P@NPs and PHX@NPs were irradiated with laser (1.0 W/cm2) while tracking temperature rise. Furthermore, photothermal stability was determined by performing five on/off cycles of irradiation and natural cooling. O2·- generation was assessed using a DPBF probe (20 μg/ml) by monitoring the absorbance at 414 nm, in a solution containing the nanoreactors (100 μg/ml) with laser (1.0 W/cm2).

2.5. Assessment of cell uptake and ROS production in vitro

Following the synthesis of indocyanine green (ICG) dye-loaded nanoreactors, P@NPs and PHX@NPs (30 μg/ml) following incubation with 4T1 cells for 12 h for analysis via flow cytometry. 4T1 cells following incubation with P@NPs and PHX@NPs (30 μg/ml) for 12 h, subsequently add DCFH-DA in fresh cell culture medium for 30 min prior to irradiation by laser (1.0 W/cm2, 5 min). Fluorescence microscopy was employed to visualize intracellular ROS production.

2.6. ICD induction and TAM repolarization evaluation in vitro

4T1 cells following incubation with PBS, P@NPs and PHX@NPs (35 μg/ml) for 12 h, then irradiated with laser (5 min). Collected cells for ICD analysis. The concentrations of extracellular ATP and HMGB1 were determined using ELISA kits. Immunofluorescence staining was performed to access calreticulin (CRT) exposure, in order to assess CRT translocation under different treatment conditions.

The M2 phenotype was first induced in Raw264.7 cells were treated with interleukin (IL)-4 (20 ng/ml) for 24 h. P@NPs and PHX@NPs (30 µg/ml) were incubated with cells under conditions with or without laser irradiation. We then established a 24 h co-culture system. Finally, the macrophage population was stained with antibodies specific for CD206, CD86, F4/80, CD11b, and analyzed using flow cytometry.

2.7. ROS, uric acid and ICD evaluation in vivo

After group-based intravenous administration of PBS, P@NPs and PHX@NPs (200 μg/ml), tumors in bilateral 4T1 models received an intratumoral injection of DCFH-DA (20 µM, 100 µl) at 24 h, irradiation by laser for 10 min. Tumors were then harvested and sectioned for fluorescence imaging to assess ROS levels.

After group-based intravenous administration of PBS, P@NPs and PHX@NPs (200 μg/ml) in bilateral 4T1 tumor-bearing mice. Following 24 h, tumor received 10 min of laser irradiation, tumors were subsequently collected, homogenized and centrifuged. Absorbance at 520 nm was measured with a uric acid test kit to determine uric acid levels.

To quantify intratumoral ICD induction, after group-based intravenous administration of PBS, P@NPs and PHX@NPs (200 μg/ml), following 24 h, primary tumors underwent irradiation for 10 min. Excised tumors were processed, ATP levels were determined using a commercial kit, immunofluorescence staining of tissue sections was performed to assess CRT and HMGB1 expression.

2.8. Assessment of pro-inflammatory factors in vivo

After group-based intravenous administration of PBS, P@NPs and PHX@NPs (200 μg/ml) in bilateral 4T1 tumor-bearing mice. Following 24 h, irradiation of tumors for 10 min. To assess cytokine expression, excised tumor tissues were analyzed for levels of IL-1β, TNF-ɑ and IL-12p70 using ELISA kits.

2.9. Assessment of M1 macrophage level and DCs maturation in vivo

After the irradiation, tumors were processed by immunofluorescence staining for the M1 macrophage markers (CD86). After intravenous administration of PBS, P@NPs and PHX@NPs (200 μg/ml), following laser irradiation of the primary tumors (10 min), the mice were euthanized on Day 10. Harvesting of tumors and tumor-draining lymph nodes was then performed. We prepared single-cell suspensions from the harvested tissues via homogenization and filtration, followed by staining with fluorescent antibodies for flow cytometry analysis.

2.10. Evaluation immune effect in vivo

Mice were subjected to intravenous administration of PBS, P@NPs, and PHX@NPs (0.2 ml, 200 μg/ml) and primary tumor laser irradiation (10 min). Tumors were harvested on Day 7 post-treatment for single-cell suspension preparation. The obtained cell suspensions were then incubated with fluorescent antibodies, followed by immunophenotypic analysis using flow cytometry.

2.11. Statistical analysis

A one-way ANOVA was used to determine statistical significance. Data are reported as mean ± SD, and the significance is denoted as *P < 0.05, **P < 0.01, ***P < 0.001.

3. Results and discussion

3.1. Preparation and characterization of PHX@NPs

A novel polymer (SP-II) possessing NIR-II characteristics was successfully synthesized, and its chemical structure was verified by 1H NMR (Fig. S1). Subsequent modification was carried out to make SP-II water‑soluble via stabilization with BSA, yielding BSA‑SP-II. Using BSA‑SP-II as a platform, the nanoreactors (PHX@NPs) were constructed through sequential thin‑film hydration and dispersion in a solution containing PFH and hypoxanthine. Further surface modification of the nanoparticles with XO yielded PHX@NPs. An optimal mass ratio of 1:2:2 (SP-II/PFH/hypoxanthine) was employed to ensure efficient loading and integration. Control nanoparticles (P@NPs) were prepared using a similar procedure without hypoxanthine and XO, in order to isolate their respective therapeutic contributions.

Successful surface modification with XO was confirmed by the BCA protein assay, which showed an encapsulation rate of 67.8% for XO in the PHX@NPs group (Fig. S2). TEM images revealed spherical nanoparticles with a uniform distribution (Fig. 2A). DLS measurements revealed comparable hydrodynamic sizes for P@NPs (29.4 nm) and PHX@NPs (31.4 nm) (Fig. 2B), and both P@NPs and PHX@NPs exhibited excellent stability, as evidenced by their consistent hydrodynamic diameters over 14 d (Fig. S3). Similar negative zeta potentials were observed for P@NPs (−15.9 mV) and PHX@NPs (−19.2 mV) (Fig. 2C). Absorbance spectra with comparable absorption and high intensity in the NIR-II region were displayed by P@NPs and PHX@NPs (Fig. 2D). A low hemolysis rate was observed for murine erythrocytes following incubation with P@NPs and PHX@NPs, demonstrating the excellent hemocompatibility and potential suitability (Fig. S4).

Fig. 2.

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Characterization of P@NPs and PHX@NPs. (A) Morphology by TEM; (B) Hydrodynamic diameter distribution profiles; (C) Measurement of zeta potential (n = 5); (D) Absorbance spectra; (E) Monitoring of temperature elevation in P@NP and PHX@NP solutions under laser; (F) Photothermal cycling stability through five consecutive 1064 nm laser irradiation and cooling cycles. (G) O2·- generation assayusing DPBF probe (n = 5); (H) Uric acid production by PHX@NPs under conditions with and without laser irradiation (n = 5).

Photothermal performance of the nanoreactors was subsequently validated. Upon laser irradiation, a gradual temperature increase was observed for both P@NPs and PHX@NPs solutions, with nearly identical temperature elevations (Fig. 2E). Excellent photostability was demonstrated by P@NPs and PHX@NPs, as evidenced by nearly unchanged heat output over five laser on/off cycles (Fig. 2F). Moreover, photothermal effect of PHX@NPs was proven to be power-dependent and concentration-dependent, with temperature rising alongside increased concentration and irradiation intensity (Fig. S5). The monitored decline in the absorbance of PHX@NPs under laser was attributed to the formation of O2·-, as monitored by the DPBF probe (Fig. S6). A progressive decrease in absorbance at 414 nm confirmed O2·- generation by PHX@NPs, which decreased by approximately 0.5-fold after 8 min of laser irradiation. No obvious variation was observed in other groups, demonstrating the specific response of PHX@NPs (Fig. 2G). Uric acid production was assessed using a uric acid assay kit. After 1064 nm laser irradiation (5 min), uric acid was clearly observed in the PHX@NPs, no production was detected in the absence of irradiation (Fig. 2H).

3.2. In vitro anticancer efficacy evaluation

The low cytotoxicity of P@NPs and PHX@NPs was confirmed by cytotoxicity assessment in 4T1 cells, where cell viability remained above 86.0% after 24 h incubation (Fig. 3A). The cellular uptake efficiency of the nanoreactors was evaluated after ICG dye loading. Flow cytometry results showed comparable fluorescence signals among the treated groups (Fig. 3B), with quantitative analysis confirming the similar uptake levels (Fig. S7). Upon 1064 nm laser irradiation, treatment with PHX@NPs led to a markedly lower cell viability (27.8%) compared to treatment with P@NPs (61.6%) (Fig. 3C), demonstrating the enhanced cytotoxic efficacy of PHX@NPs under photothermal conditions.

Fig. 3.

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In vitro efficacy assessment. (A) 4T1 cell viability following the treatments with P@NPs and PHX@NPs (n = 5); (B) Flow cytometry analysis of 4T1 cells after P@NPs and PHX@NPs treatment; (C) Cell viability following co-training with P@NPs and PHX@NPs (30 μg/ml) and with or without laser (n = 5, ***P < 0.001); (D) ROS levels in 4T1 cells incubation with P@NPs and PHX@NPs with or without laser; (E) Immunofluorescence staining for CRT assessment across differentially groups; (F) Flow cytometry analysis of macrophages across all the treatment groups; (G) Ratio of M1/M2 across treatment groups (n = 5, ***P < 0.001); (H) Determination of uric acid concentration across all groups (n = 5, ***P < 0.001); (I) Analysis of IL-1β expression across all groups (n = 5, **P < 0.01 and ***P < 0.001).

ROS generation within 4T1 cells was evaluated by measuring fluorescence intensity using a fluorescent probe (DCFH-DA). After incubation with PHX@NPs + laser, strong fluorescence was detected, verified the ROS production (Fig. 3D). No significant fluorescence was detected in other groups. A 4.0-fold higher fluorescence intensity was observed in PHX@NPs group compared to P@NPs group (Fig. S8). These confirmed that the PHX@NPs + laser treatment induced ROS generation, and that the production of superoxide anions was specifically promoted by the irradiation.

Subsequently, ICD was assessed by measuring CRT exposure, extracellular ATP secretion, and HMGB1 release. Confocal microscopy revealed that distinct CRT-specific fluorescence was prominently exposed on the 4T1 cells following treatment with PHX@NPs + laser irradiation, whereas fluorescence signals were barely detectable in other groups (Fig. 3E). Quantitative fluorescence analysis verified that laser irradiation enhanced the fluorescence intensity in both P@NPs and PHX@NPs treated groups, with the PHX@NPs group exhibiting the highest intensity —representing a 2.5-fold rise in comparison with the P@NPs group (Fig. S9). Without laser irradiation, no significant differences observed in ATP levels among any of the groups (Fig. S10). Upon laser irradiation, significantly increased ATP concentrations were observed in the PHX@NPs group, which showed a 3.9-fold increase relative to PBS group. When without laser irradiation, no significant differences in HMGB1 concentration between the groups. Following laser irradiation, the PHX@NPs + laser group showed the highest HMGB1 concentration, demonstrating a 4.2-fold and a 6.0-fold increase compared to P@NPs + laser and PBS + laser groups, respectively (Fig. S11). In summary, the recruitment of antigen-presenting cells driven by CRT exposure, combined with the adjuvant effects of ATP and HMGB1 secretion, collectively led to improved tumor antigen presentation.

Following laser irradiation, the nanoreactors decomposed and subsequently generated uric acid via an enzymatic reaction. Post-irradiation analysis revealed that the PHX@NPs group exhibited the highest uric acid content, significantly exceeding that of all the other groups, thereby confirming the effective production of uric acid (Fig. 3H). Notably, the production of uric acid further triggers the secretion of pro-inflammatory cytokines from macrophages. This process drives induces M1 polarization of macrophages and promotes immunostimulatory effect, thus activating immune cells. Flow cytometry analysis was employed to systematically validate macrophage polarization. Macrophage phenotypes was analyzed via flow cytometry based on CD206+and CD86+ expression. As shown in Fig. 3F, the transition from M2 to M1 phenotype was demonstrated, with M1 macrophage phenotype (CD86+ CD206-) being detected at 30.0% in PHX@NPs + laser group. Under identical conditions, this rate was significantly higher compared to the considerably lower rates of only 9.3% and 4.3% perceived in the P@NPs + laser and PBS + laser groups, respectively. Furthermore, the M2 phenotype (CD86-CD206+) was significantly downregulated in the PHX@NPs + laser group, reaching 15.8%. This contrasted markedly with the levels perceived in the P@NPs + laser and PBS + laser groups, which remained high at 32.8% and 31.9%, respectively. Quantitative analysis revealed a significantly increased M1/M2 macrophage ratio in PHX@NPs + laser group, which was 3.6- and 12.3-fold higher than that in P@NPs + laser and PBS + laser groups, respectively (Fig. 3G). This shift was associated with the uric acid generation, driving the M2-to-M1 repolarization of macrophages. Finally, the IL-1β expression was examined. Notably, IL-1β expression in the PHX@NPs + laser group was 3.2-fold higher than in the P@NPs + laser group (Fig. 3I).

3.3. Antitumor efficacy in vivo

The photothermal of the nanoreactors was assessed by real-time thermal imaging to monitor the intratumoral temperature dynamics., After irradiated with laser under the condition of 0.4 W/cm2, the treated groups exhibited a rapid temperature increase. The P@NPs and PHX@NPs groups exhibited higher peak temperatures (42.1 °C and 42.2 °C) than the PBS group (37.7 °C) (Fig. S12).

To investigate the tumor accumulation, the nanoreactors were labeled with ICG. After intravenous administration of P@NPs and PHX@NPs, the tumor site fluorescence intensity was monitored. It was observed that the tumor fluorescence intensity gradually increased between 0–24 h and subsequently decreased between 24 and 36 h (Fig. 4A). Maximum accumulation of P@NPs and PHX@NPs was achieved at 24 h post-injection (Fig. 4B). Biodistribution studies in harvested organs revealed that these nanoreactors were primarily accumulated in the tumor tissues, while the minimal deposition was detected in other tissues (Fig. 4C). Quantitative assessment of the isolated tissues further confirmed this distribution profile, demonstrating that P@NPs and PHX@NPs exhibited the most pronounced tumor localization (Fig. S13).

Fig. 4.

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Antitumor efficacy in vivo. (A) ICG-labeled nanoreactors were imaged in mice at indicated time points (0–36 h) post-injection; (B) Time‑dependent monitoring of tumor fluorescence intensity. (n = 5); (C) Biodistribution fluorescence imaging in tumors and organs; (D) 4T1 tumor-bearing mice experimental design; (E) Primary tumor volumes across all groups at indicated time points (n = 5, ***P < 0.001); (F) Distant tumor volumes across all groups at indicated time points (n = 5, ***P < 0.001); (G) Analysis of survival rate during 40-d (n = 5, ***P < 0.001); (H–I) H&E staining of primary and distant tumors.

Given the ICD effect and systemic antitumor immunity induced by nanoreactor-based therapy, the therapeutic efficacy against tumors was evaluated. A bilateral 4T1 mice model was established, and systematic evaluation was performed over a 40-d treatment period (Fig. 4D). After treatment, obvious inhibition of primary tumors was noticed in PHX@NPs + laser group (Fig. 4E). Analysis of tumor volume and calculation of the tumor growth inhibition rate revealed that PHX@NPs + laser group demonstrated the optimal antitumor efficacy, achieving an inhibition rate of 91.2%. In contrast, inhibition rates of 38.3% and 11.7% were recorded for P@NPs + laser and PBS + laser group, respectively (Fig. S14). During monitoring of distant tumors growth, it was suppressed in the group injected with PHX@NPs combined with laser treatment (Fig. 4F). The tumor inhibition rates were calculated, revealing that among the treatment groups, the PHX@NPs + laser group showed the best antitumor efficacy with the highest inhibition rate reaching 99.9%, while the P@NPs + laser group tumor inhibition rate was 44.6% (Fig. S15). Throughout the entire treatment period, an excellent therapeutic effect was consistently maintained, and data analysis for the whole experiment was confirmed to be statistically significant. The mice body weights were continuously recorded during the therapy time, no significant changes were observed, indicating that the treatment was well-tolerated (Fig. S16).

Mouse survival was tracked during 40-d. After treatment, all animals in PHX@NPs + laser group survived, achieving a survival rate of 100% (Fig. 4G). This outcome was superior to the survival rates observed in P@NPs + laser group (20%), PBS + laser group (0%) and PHX@NPs group (0%), further demonstrating the excellent therapeutic efficacy. To assess the therapeutic efficacy, primary and distant tumors were subjected to H&E staining (Fig. 4H−4I). The tumors in the PHX@NPs + laser group were characterized by extensive apoptosis, whereas those in the PBS group exhibited only minimal apoptotic activity. Compared with the P@NPs + laser group, the greatest induction of apoptotic was seen in the PHX@NPs + laser group. These results further verified that the strongest antitumor efficacy was achieved through the PHX@NPs-mediated combination therapy.

3.4. Anti-metastatic efficacy and mechanism evaluation in vivo

Bilateral subcutaneous 4T1 tumor models were established, followed by a systematic assessment after a 30-d therapeutic period (Fig. 5A). Upon completion of the 30-d therapeutic regimen, quantitative assessment of anti-metastatic efficacy mediated by nanoreactors-based treatment was conducted. Histopathological analysis of lung tissues revealed that minimal metastatic nodules were noticed in the PHX@NPs + laser group, whereas a certain number of metastatic nodules remained present in all other experimental groups (Fig. 5B). Statistically significant differences among the treatment groups were further revealed by quantitative assessment. It was noteworthy that the PHX@NPs + laser group exhibited marked suppression of lung metastasis compared with the PBS group. Quantitative analysis verified that the average numbers of metastatic nodules in the P@NPs + laser and the PHX@NPs + laser groups were 10.7 and 1.3, respectively (Fig. 5C). Similarly, histopathological examination of H&E-stained liver tissue sections revealed that hepatic metastasis was significant suppressed in the PHX@NPs + laser group. Notably, the PHX@NPs + laser group showed minimal metastatic nodules (Fig. 5D). Quantitative analysis indicated that the average numbers of metastatic nodules in the P@NPs + laser and PHX@NPs + laser groups were 16.3 and 2.0, respectively (Fig. 5E). Additionally, H&E staining of heart, spleen and kidney disclosed no statistically significant alterations between PBS and PHX@NPs + laser group, confirming the safety profile of the nanoreactors (Fig. S17). The excellent therapeutic efficacy of PHX@NPs was validated through metastatic analysis of liver and lungs, demonstrating effective tumor treatment while simultaneously suppressing metastasis.

Fig. 5.

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In vivo anti-metastatic efficacy and mechanism evaluation. (A) Experimental design of mouse models for anti-metastatic efficacy evaluation; (B) H&E staining of lung tissue; (C) Evaluation of lung metastatic across all treatment groups (n = 5, ***P < 0.001); (D) H&E staining of liver tissue; (E) Quantitative evaluation of liver metastatic across all groups (n = 5, *** P < 0.001); (F) Detection of ROS production in primary tumors across all treatment groups; (G) Detection of uric acid production in primary tumors across all treatment groups (n = 5, ***P < 0.001).

Fluorescence imaging confirmed the presence of ROS in tumor tissues. Green fluorescence, indicative of ROS production, exhibited the strongest intensity in the PHX@NPs + laser group. This further confirmed that the enzymatic reaction leading to superoxide anion production could be triggered upon laser irradiation (Fig. 5F). Quantitative analysis disclosed that the ROS green fluorescence signal intensity in the PHX@NPs + laser group showed a 7.6-fold increase compared to the P@NPs + laser group (Fig. S18).

To validate the uric acid generation at the tumor site, primary tumor tissues were homogenized post-treatment, and the supernatant analysis was performed using a specific assay kit. The results indicated elevated uric acid levels in the PHX@NPs + laser group, showing approximately 63.8-fold, 63.8-fold and 118.6-fold increases compared with P@NPs + laser, PBS + laser, and PHX@NPs group, respectively (Fig. 5G). These findings provided compelling evidence that laser irradiation effectively triggered the uric acid production, highlighting the superiority of the combined therapeutic approach.

3.5. Assessment of macrophage polarization and ICD in vivo

The ICD effect was evaluated following respective treatments. Upon administration of P@NPs and PHX@NPs combined with laser irradiation, primary tumors showed positive red fluorescence for CRT and HMGB1, with PHX@NPs + laser group exhibiting the strongest fluorescence, while almost no signal was observed in the other groups (Fig. 6A). CRT and HMGB1 signal intensities were markedly enhanced in the PHX@NPs + laser group as opposed to the P@NPs + laser. CRT fluorescence intensity increased 2.5-fold in the PHX@NPs + laser group versus the P@NPs + laser group. Similarly, HMGB1 fluorescence intensity increased 2.8-fold in the PHX@NPs + laser group versus the P@NPs + laser group (Fig. S19). ATP levels increased significantly after P@NPs + laser and PHX@NPs + laser treatment. PHX@NPs + laser group exhibited the highest ATP concentration. Quantitative analysis revealed that the ATP concentrations in PHX@NPs + laser group was 2.2-fold higher than that in P@NPs + laser group (Fig. S20).

Fig. 6.

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Assessment of ICD and macrophage polarization in vivo. (A) CRT and HMGB1 expression in tumors assessed by immunofluorescence across treatment groups; (B–D) Levels of IL-1β, TNF-ɑ and IL-12p70 in tumors after treatments (n = 5, ***P < 0.001); (E–F) M1 and M2 macrophages immunofluorescence images in primary tumor and distant tumor tissues.

Subsequently, the pro-inflammatory cytokines expression was examined. Following intravenous administration of nanoreactors combined with laser treatment, a significant upregulation of pro-inflammatory cytokines was observed, with the most pronounced effect detected in the PHX@NPs + laser group. This enhanced response could be attributed to the effective generation of uric acid from nanoreactors fragmentation post-irradiation, indicating potent augmentation of the antitumor immune response. Relative to P@NPs + laser, PHX@NPs + laser increased IL-1β, TNF-ɑ and IL-12p70 expression by 3.1-fold, 4.2-fold and 4.4-fold, respectively (Fig. 6B–6D).

Finally, the immunofluorescence staining in the tumors was performed to detect M1 and M2 macrophage markers. The PHX@NPs + laser group showed the strongest M1 fluorescence intensity in primary and distant tumors, while the other groups were barely detectable. Uric acid could activate the NLRP3 inflammasome in macrophages, promoting shift M2 macrophages toward the M1 phenotype (Fig. 6E–6F). The M1 fluorescence intensity was increased by 3.3-fold in the PHX@NPs + laser group compared to the P@NPs + laser group in primary tumors (Fig. S21). Similarly, the M1 fluorescence intensity was increased by 4.3-fold in the PHX@NPs + laser group compared to the P@NPs + laser group in distant tumors (Fig. S22).

3.6. Immune response evaluation in vivo

DCs maturation and immune cells infiltration was evaluated across different treatment groups. The results demonstrated that treatment with nanoreactors with laser irradiation induced the significantly enhanced maturation of DCs compared to PBS group (Fig. 7A and S23). Quantitative analysis revealed the proportion of matured DCs reached 51.2% in PHX@NPs + laser group, 35.3% in P@NPs + laser group and 18.1% in PBS + laser group.

Fig. 7.

Fig 7 dummy alt text

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Immune response assessment in vivo. (A) Mature DCs in lymph nodes; (B-C) CD3+CD4+ T cells in primary tumors and distant tumors; (D-E) CD3+CD8+ T cells in primary tumors and distant tumors; (F-G) Analysis of M1 and M2 macrophages in the primary tumors; (H-I) Analysis of M1 and M2 macrophages in distant tumors. n = 5, **P < 0.01, ***P < 0.001.

T cell populations in tumors were analyzed to further assess the immune activation effects of the different treatments. In primary tumors, compared to the PBS group, an obvious increase in CD3+CD4+ T cells was detected in P@NPs + laser and PHX@NPs + laser groups. The PHX@NPs + laser group showed the highest proportion at 38.2%, followed by 27.8% in the P@NPs + laser group and 10.9% in the PBS + laser group. The PHX@NPs + laser group showed a 1.4-fold higher proportion than the P@NPs + laser group (Fig. 7B and S24). A similar phenomenon was observed in distant tumors, where PHX@NPs + laser treatment resulted in the highest proportion of CD3+CD4+ T cells at 39.3%, compared to 31.9% in the P@NPs + laser group, and 12.5% in the group of PBS + laser. The PHX@NPs + laser group showed a 1.2-fold higher proportion than the P@NPs + laser group (Fig. 7C and S25). Regarding cytotoxic T cells, the levels of CD3+CD8+ T cells were evaluated. CD3+CD8+ T cell infiltration in primary tumors increased in PHX@NPs + laser and P@NPs + laser groups compared to PBS group. The PHX@NPs + laser group showed the highest proportion at 45.0%, followed by 30.0% in P@NPs + laser group and only 11.9% in PBS + laser group. The PHX@NPs + laser group showed a 1.5-fold higher proportion than the P@NPs + laser group (Fig. 7D and S26). A similar trend was observed in distant tumors, where the treated groups also exhibited higher levels than the PBS group. The CD3+CD8+ T cell infiltration was 47.7% in the PHX@NPs + laser group, 34.4% in the P@NPs + laser group, and 12.0% in the PBS + laser group. The proportion in the PHX@NPs + laser group was 1.4-fold higher than that in the P@NPs + laser group (Fig. 7E and S27). These results indicated that the PHX@NPs + laser treatment most effectively boosted tumoral T cells infiltration, demonstrating its unique potential for tumor immunotherapy. Finally, the polarization reversal of tumor-associated macrophage was evaluated. In the primary tumors, compared with PBS + laser and P@NPs + laser groups, the CD206+ in the PHX@NPs + laser group was significantly reduced to 3.2%, while the CD86+ population was markedly enhanced to 23.0% (Fig. 7F, 7G and S28). A shift in the macrophage profile from CD206+ to CD86+ was also observed in distant tumors following PHX@NPs + laser treatment. Compared with the PBS + laser and P@NPs + laser groups, the proportion of CD206+ macrophages in distant tumors were decreased to 3.2% in the PHX@NPs + laser group, while the proportion of CD86+ cells were elevated to 22.0% (Fig. 7H, 7I and S29). These findings verified that macrophage repolarization was effectively promoted by the uric acid-producing PHX@NPs upon laser irradiation.

4. Conclusion

A programmable nanoreactor (PHX@NPs) was designed for photothermal immunotherapy via NIR-II triggered enzyme‑catalyzed immunogenic tumor microenvironment remodeling. PHX@NPs were composed of a novel synthesized semiconducting polymer, along with PFH and hypoxanthine, and their surface was modified with XO. Due to the presence of the semiconducting polymer, an excellent PTT effect was exhibited by PHX@NPs. This design enabled the on-demand, light-triggered release of O2·- and uric acid directly within tumors. Locally generated O2·- and uric acid, triggering tumor cell death and inducing ICD, promoted the tumor-associated macrophage repolarization and upregulated the expression of pro-inflammatory factors, thereby activating a robust immune response and enhancing antitumor efficacy. In the bilateral 4T1 tumor mouse models, effective suppression of tumor growth was achieved following intravenous administration of PHX@NPs combined with laser irradiation, with a remarkable inhibition rate of up to 99% observed in distant tumors. Furthermore, tumor metastasis to the liver and lungs was almost completely suppressed, and the therapeutic efficacy was significantly superior to that of the control groups. This study provides a promising nanoplatform for effective cancer treatment, capable of autonomously executing complex biological functions upon a single external stimulus. Future studies should also explore the compatibility of this platform with established immunotherapies to determine whether synergistic combinations can further enhance therapeutic outcomes without exacerbating toxicity.

Conflicts of interest

The authors declare that there is no conflicts of interest.

Acknowledgements

This research was supported by the Natural Science Foundation of Fujian Province (grant 2025J010047), Donghua University 2024 Cultivation Project of Discipline Innovation, DHU Distinguished Young Professor Program Under Grant LZB2025003, and the Science and Technology Commission of Shanghai Municipality (20DZ2254900).

Footnotes

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2026.101150. The figures and tables with “S” before the serial number are included in the Supplementary materials.

Contributor Information

Jingyang Su, Email: jysu@cmu.edu.cn.

Jingchao Li, Email: jcli@dhu.edu.cn.

Appendix. Supplementary materials

Supplementary materials

mmc1.docx (18.9MB, docx)

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