蛋白质载体和多糖载体作为生物大分子载体，凭借优异的生物相容性、生物可降解性及独特的生物活性，已广泛地应用于抗肿瘤药物递送系统（drug delivery systems，DDSs）。通常，抗肿瘤药物可通过共价修饰或非共价结合的方式负载至生物大分子载体上。非共价载药策略（如氢键、亲疏水作用、范德华力等）的操作简单且普适性强，但其药物负载的稳定性差，且释药性能难以精确调控。相比之下，共价载药策略则通过化学反应将药物与载体直接键合，不仅提高了药物的负载稳定性，还可通过设计响应性连接键响应肿瘤微环境（tumor microenvironment，TME）的物理化学刺激，以实现TME响应性药物释放。 肿瘤光疗是近年来新兴的肿瘤治疗方法，其利用光能对肿瘤组织进行治疗，主要包括光热治疗（photothermal therapy，PTT）和光动力治疗（photodynamic therapy，PDT）。PTT通过光热剂（photothermal agents，PTAs）吸收近红外光的光能并将其转化为热能，利用热能杀伤肿瘤；而PDT则通过特定波长的光源激发光敏剂生成活性氧（reactive oxygen species，ROS）杀伤肿瘤。然而，由于光疗药物存在能量转化效率低、药物在肿瘤的递送效率不高、激光穿透深度有限以及单一治疗效果不佳等问题，导致肿瘤光疗在体内的治疗效果欠佳。本论文从上述问题出发，基于生物大分子载体开发了两种DDSs用于提升肿瘤光疗的治疗效果。 本论文首先设计了一种人血清白蛋白（human serum albumin，HSA）-双马来酰亚胺交联策略，以提高HSA制剂的载药量和药物递送效率。氮杂氟硼二吡咯（aza-boron-dipyrromethene，aza-BODIPY）类光热剂具有较高的光热转化效率，我们基于该母核结构合成了具有双马来酰亚胺结构的小分子光热剂BPY-Mal2。进一步，我们通过三(2-羧乙基)膦（tris(2-carboxyethyl)phosphine，TCEP）还原HSA制得了含有游离巯基的HSA-SH，通过马来酰亚胺基团与巯基的Michael加成反应，将BPY-Mal2共价结合至HSA链上，以形成交联纳米制剂BPY@HSA。与直接将药物负载至HSA上的制剂BPY-HSA相比，BPY@HSA通过显著增加HSA载体可用于负载药物的巯基数量，提升了药物载量（达26.1%），显著高于传统制剂方法。此外，BPY@HSA不仅能通过更多的摄取通路进入肿瘤细胞，还能结合更多的白蛋白受体（gp18和gp30），增强了在乳腺癌模型中的药物递送效率，进而表现出更好的PTT效果。 为进一步解决光在肿瘤组织穿透性的问题，本论文还以葡聚糖为载体，通过共价修饰策略构建了共负载ROS响应性紫杉醇（paclitaxel，PTX）前药、光敏剂Ce6和鲁米诺的葡聚糖胶束PCL-NPs。PCL-NPs中的鲁米诺在过氧化氢的存在下可发生化学发光，其能量可由化学发光共振能量转移（chemiluminescence resonance energy transfer，CRET）传递至Ce6，实现内部光源介导的化学发光PDT，进而解决了外部光源在肿瘤组织穿透深度有限的问题。在该体系中，Ce6激活后生成的单线态氧（1O2）不仅能直接杀伤肿瘤组织，还能激活ROS响应性PTX前药的释放，从而实现化学发光PDT与化疗的联合治疗。 综上，本论文通过设计能量转化效率高的光敏剂、开发肿瘤药物递送效率高的DDSs、利用化学发光作为内部光源引发PDT和联合化疗等策略，提升了肿瘤光疗的治疗效果，为肿瘤光疗的进一步研发和应用提供了新的范式。

The protein carriers and polysaccharide carriers, as biomacromolecule carriers, have been widely used in anticancer drug delivery systems (DDSs) due to their excellent biocompatibility, biodegradability, and unique biological activity. Typically, anti-tumor drugs could be loaded onto the biomacromolecule carriers through covalent modification or non-covalent interactions. Non-covalent strategies utilize intermolecular forces such as hydrogen bonds, hydrophobic interactions, and van der Waals forces to load drugs onto carriers. Although such strategies are simple and convenient, they result in poor drug loading stability and uncontrollable drug release performance. In contrast, covalent loading strategies directly connect drugs to carriers through chemical reactions, not only improving drug loading stability but also allowing the incorporation of responsive linkers that react to physical and chemical stimuli in the tumor microenvironment (TME) for TME-responsive drug release. Tumor phototherapy, an emerging treatment method in recent years, utilizes light energy to treat tumor tissues, primarily involving photothermal therapy (PTT) and photodynamic therapy (PDT). PTT employs photothermal agents (PTAs) to absorb near-infrared light energy and convert it into heat, which is then used to kill tumor tissue. PDT, on the other hand, activates photosensitizers with light of specific wavelengths to generate reactive oxygen species (ROS) to kill tumors. However, the low energy conversion efficiency of phototherapeutic drugs, the poor drug delivery efficiency in tumors, and the limited penetration depth of lasers in tissues result in unsatisfactory therapeutic effects in vivo. In response to these limitations, this thesis developed two types of DDSs based on biomacromolecule carriers to improve the therapeutic efficacy of tumor phototherapy. This thesis first designed a human serum albumin (HSA)-maleimide crosslinking strategy to enhance the drug loading and delivery efficiency of HSA-based formulations. Aza-BODIPY (aza-boron-dipyrromethene) photothermal agents, with high energy conversion efficiency, were selected as the core structure to synthesize the small molecule photothermal agent BPY-Mal2. Further, HSA materials with abundant free thiol groups (HSA-SH) were obtained by reducing HSA with tris(2-carboxyethyl)phosphine (TCEP). Next, BPY-Mal2 was then covalently conjugated to the HSA chain through a Michael addition reaction with maleimide groups to form crosslinked nanoparticle formulation BPY@HSA. Compared to the direct loading of drugs into HSA (BPY-HSA formulation), BPY@HSA significantly increased the number of thiol groups available for drug loading, resulting in a drug loading capacity of 26.1%, which was much higher than that of other similar HSA formulations. In addition, BPY@HSA exhibited enhanced cellular uptake via multiple uptake pathways and albumin receptors (gp18 and gp30), and showed improved drug delivery efficiency in a breast cancer model, thereby presenting superior photothermal therapeutic effects. To further address the issue of light penetration in tumor tissues, dextran-based micelles (PCL-NPs) co-loaded with ROS-responsive paclitaxel (PTX) prodrug, photosensitizer Ce6, and luminol were constructed through covalent modification strategies. In the presence of hydrogen peroxide, luminol underwent chemiluminescence, and its energy was transferred to Ce6 via chemiluminescence resonance energy transfer (CRET), thereby triggering PDT with internal light sources. This approach overcame the limitations of external light source penetration in tumor tissues. In this system, the singlet oxygen (1O2) generated by the activation of Ce6 not only killed tumor tissues directly but also triggered the release of ROS-responsive PTX prodrug, thereby enabling a combination of chemiluminescence PDT and chemotherapy. In summary, this thesis enhanced the therapeutic efficacy of tumor phototherapy by designing photosensitizers with high energy conversion efficiency, developing efficient tumor-targeted drug delivery systems, employing chemiluminescence as an internal light source to initiate PDT, and integrating combination chemotherapy strategies, which provided new paradigms for the further development and application of tumor phototherapy.