Cancer is one of the critical factors in death, which severely menace human health and life [[1], [2], [3], [4]]. As one of the most effective means, chemotherapy has achieved excellent accomplishment in clinical treatment by using chemotherapeutics to kill cancer cells directly. Unluckily, owing to the unavoidable side effects, drug tolerance, poor selectivity, and the complicacy and heterogeneity of malignant tumors, chemotherapy usually fails to achieve a gratifying curative result [[5], [6], [7]]. To address these challenges, all kinds of drug carriers such as liposomes, hydrogels, fibers, etc. have been extensively developed in the field of tumor treatment over the past decade [[8], [9], [10], [11], [12], [13], [14]]. Despite the excellent results and practices, these drug carriers still face many limitations. The simple drug packages may result in premature and rapid drug release, leading to low bioavailability of drugs. Besides, the commonly used synthetic polymers for preparing these carriers typically involve complicated synthesis procedures and additional additives, which can lead to a cumbersome preparation process and unwanted toxicity. Instead, organism-derived materials have the merits of outstanding biocompatibility and convenient access for biomedical applications [[15], [16], [17]]. Accordingly, the development of a novel hierarchical drug delivery system with naturally derived biopolymer for effective drug loading and release possesses promising clinical application potential in cancer therapy.

In this paper, we presented novel hierarchical mesoporous silicon nanoparticles (MSNs) and bovine serum albumin (BSA) composited microparticles to achieve the required multifarious functions for effective tumor therapy, as schemed in Fig. 1. On the one hand, MSNs have attracted wide attention in the domain of oncology and biomedicine in the last decades [[18], [19], [20], [21], [22], [23]]. As a kind of excellent nano-delivery carrier, MSNs possess a large surface area to provide numerous drug-loading sites. Therefore, MSNs have been widely used to carry various chemotherapeutic drugs such as doxorubicin (DOX), and 5-fluorouracil (FU) for tumor treatment [[24], [25], [26], [27], [28]]. On the other hand, BSA is a type of organism-derived protein with superb biocompatibility and biodegradability. Intriguingly, it is also featured by high drug-binding capacity, non-immunogenicity, and evading the immune system [[29], [30], [31], [32], [33]]. Thus, the effective integration of MSNs and BSA to fabricate a new drug packaging system that could realize the sustained release of drugs and largely avoid the systemic toxicity of chemotherapeutics is still anticipated.

Herein, hierarchical hydrogel microparticles based on MSNs and BSA loaded with DOX and FU were developed via droplet microfluidics. Microfluidic technique has become a universal platform for synthesizing diversified nano or micromaterials; these materials have been extensively applied in biomedical research such as tumor therapy, drug delivery, etc. Compared with conventional methods, microfluidic-based microparticle production has marked advantages including adjustable size, superior reproducibility, and efficient encapsulation rate. In this study, two kinds of anti-cancer medicines, DOX and FU were first embarked into the MSNs completing the preparation of MSNs@DOX/FU. Besides, BSA was simply modified with methacrylic anhydride into a photo-crosslinkable polymer (BSAMA). By applying the microfluidic technique, the MSNs@DOX/FU combined with BSAMA could obtain the required hierarchical hydrogel microparticles (named MPMSNs@DOX/FU). Notably, the special hierarchical structure of this drug delivery system renders the slow release of DOX and FU from MSNs owing to the gradual degradation of the outer layer of the BSAMA matrix. Thus, the obtained MPMSNs@DOX/FU will act as a drug reservoir after injection in the tumors, achieving a long-term therapeutic effect on cancer cells. Based on these merits, the MPMSNs@DOX/FU demonstrated a notable killing effect on liver cancer cells in vitro and a distinct inhibition action to the liver cancer model in vivo with good safety. These fascinating features award the hierarchical MPMSNs@DOX/FU with promising potential in tumor therapy.