In this paper, the authors present a polymeric microparticle (MP)-based for the slow and controlled release of IL-1α to suppress the acute pro-inflammatory side effects of systemically delivered IL-1α. While the hypothesis presented by the authors is intriguing and perhaps may be of high therapeutic value, several critical experiments are missing and needed to further validate this work.

1) In figure 1, the authors normalized the data to the control group. The baseline activation of these cell lines is important to understand the effect of IL-1α. Therefore, this reviewer suggests not normalizing the results. In addition, the authors only tested free rIL-1α. To confirm that the IL-1α is functional once is encapsulated into the microparticle, the IL-1α-MP and the empty-MP groups should be also tested.

2) In figure 3, the authors reported a significant body weight when free IL-1α was administrated. Can the authors explain why the body weight loss only occurs in the first injection (day 5) and not in the second one (day 9)?

3) To confirm that IL-1α-MPs produce less acute toxicity, ALP, AST, TBIL, and creatine serum biomarkers should be tested at earlier time points (1-2 days post-injection).

4) In Figure 3D, is the CPH:Sa-IL-1 group significantly different from the CPH:Sa blank group?

5) Are the MIP-1b and IL-9 cytokine levels between IL-1α-MPs and blank-MPs significantly different? If not, how do the authors explain the mechanism of action of these IL-1α-MPs?

6) Why different IL-1α / MPs ratios were used between experiments? The authors reported that 29.4 mg of MPs were used to deliver 3.5 ug of IL-1α. However, to deliver 7.5 ug of IL-1α only 10.7mg MPs were needed.

7) In Figure 7, the authors observed an increase in the number of tumor-infiltrating immune cells when the mice were treated with rIL-1α or IL-1α-MP. Could the authors justify why 15ug of rIL-1α was used for this experiment? In addition, it will be interesting to test different time points (2 days after treatment vs 7 days) to confirm differences in the temporal activation of immune cells due to the sustained release of IL-1α from the microparticles.

8) IL-1α-MPs biodistribution and pharmacokinetic study will help to understand the IL-1α sustain release in vivo.

Minor additional comments:

1) There are some details in the materials and methods part that are missing. Is the 1,6-bis-(p-carboxyphenoxy)-hexane: sebacic 20:80 polymer synthesized by the authors? If not, please specify from where this polymer was obtained. Also, the molecular weight of this polymer should be reported.

2) Provide information on the fluorophores used for each flow cytometry antibody. I will suggest adding the gating strategy in the supporting information.

3) Supplemental Figure 3 is missing.

4) The authors should clarify when the blood for cytokine expression was collected, on Day 10 (after the second injection) or day 6 (after the first injection).

This reviewer thinks that the paper's hypothesis is interesting and can have an important therapeutic value. However, at this point, there is not enough evidence to support the author's hypothesis. The following points should be addressed:
- The authors design an IL-1a-microparticles to suppress the acute pro-inflammatory side effects of free IL-1a by allowing for slow and controlled release of IL-1α systemically. Unfortunately, there is not enough evidence to support this claim.
- The CPH:SA-IL-1a-MPs functionality should be tested at in vitro level. Cytokines can rapidly lose their activity once they are encapsulated by biomaterials. Indeed, the efficacy data (Figure 6) show no statistical difference between the empty vehicle microparticle and the CPH:SA-IL-1a-MPs.
- The authors claim that significant differences were observed when higher doses of CPH:SA-IL-1a-MPs were used compared to blank CPH:SA-MPs, however, this data is not supported by Figure 6.
- Different CPH:SA-IL-1a-MPs formulations were used across the paper, which makes it difficult to compare the data across experiments. To be able to compare the data the same protocol to synthesize the CPH:SA-IL-1a-MPs should be used.
- The body weight loss justification in Question 3 is unclear. This reviewer understands that the authors do not have the body weight data for treatment days 2 and 3. However, this reviewer thinks that this data is crucial. Without this data, this figure is confusing and difficult to understand for future readers

The authors addressed most of the comments.